IL-17 receptor A antigen binding proteins

ABSTRACT

The present invention relates to IL-17 Receptor A antigen binding proteins, such as antibodies, and compositions and methods for diagnosing and treating diseases mediated by IL-17 Receptor A activation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/906,094, filed Sep. 28, 2007, now U.S. Pat. No. 7,939,070, whichclaims the benefit under 35 U.S.C.1 §119 of U.S. Provisional ApplicationSer. No. 60/969,895, filed Sep. 4, 2007, U.S. Provisional ApplicationSer. No. 60/873,072, filed Dec. 5, 2006 and U.S. Provisional ApplicationSer. No. 60/827,882, filed Oct. 2, 2006, which are hereby incorporatedby reference.

REFERENCE TO SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledA-1116-US-DIV4_seq_listing.txt, created Mar. 4, 2011, which is 209 KB insize. The information in the electronic format of the Sequence Listingis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to IL-17 Receptor A (IL-17RA or IL-17R)antigen binding proteins, such as antibodies, and compositions andmethods for diagnosing and treating diseases mediated by IL-17 ReceptorA activation by one or more IL-17 ligands.

BACKGROUND

IL-17A is an inflammatory cytokine initially identified as a transcriptselectively expressed by activated T cells. IL-17RA is a ubiquitouslyexpressed and shown to bind IL-17A with an affinity of approximately 0.5nM (Yao et al., 1995, Immunity 3:811-821). Five additional IL-17-likeligands (IL-17B-IL-17F) and four additional IL-17RA-like receptors(IL-17RB-IL-17RE) have been identified (Kolls and Linden, 2004, Immunity21:467-476).

IL-17RC has been shown to bind IL-17A and L-17F. The observations thatIL-17RA deficiency and IL-17RA antibody neutralization ablate bothIL-17A and IL-17F function suggest that IL-17RC cannot deliver an IL-17Aor IL-17F signal in the absence of IL-17RA (Toy et al., 2006, J.Immunol. 177:36-39; McAllister et al., 2005, J. Immunol. 175:404-412).Additionally, forced expression of IL-17RC in IL-17RA deficient cellsdoes not restore IL-17A or IL-17F function (Toy et al., 2006, J.Immunol. 177:36-39).

IL-17A and IL-17F are predominantly expressed by activated CD4⁺ memory Tcells (Kolls and Linden, 2004, supra). It has been proposed that anIL-17A-producing pathogenic CD4+ T cell subset, ThIL-17, is expanded inthe presence of IL-23 (Langrish et al., 2005, J. Exp. Med. 201:233-240).Additionally, both IL-15 and the TNF superfamily member OX40L have beenshown to induce the expression of IL-17A (Nakae et al., 2003b, Proc.Natl. Acad. Sci. U.S.A. 100:5986-5990; Ziolkowska et al., 2000, J.Immunol. 164:2832-2838). IL-6 and TGF-beta also induce the expression ofIL-17A.

IL-17A and IL-17F bind and activate IL-17RA. IL-17RA has been shown tobe important in regulating immune responses. Activation of the IL-17RAleads to production of cytokines, chemokines, growth factors, and otherproteins that contribute to the symptoms and/or pathology of numerousdiseases. IL-17A is an inflammatory cytokine that induces the productionof cytokines and other mediators leading to diseases and physiologicaleffects such as inflammation, cartilage degradation, and boneresorption. IL-17A also plays a role in a number of inflammatoryconditions including arthritis (rheumatoid arthritis), psoriasis,inflammatory bowel disease, multiple sclerosis, and asthma. (Li et al.,2004, Huazhong Univ. Sci. Technolog. Med. Sci. 24:294-296; Fujino etal., 2003, Gut. 52:65-70; Kauffman et al., 2004, J. Invest. Dermatol.123:1037-1044; Mannon et al., 2004, N. Engl. J Med. 351:2069-2079;Matusevicius et al., 1999, Mult Scler 5, 101-104; Linden et al., EurRespir J. 2000 May; 15(5):973-7; Molet et al., 2001, J. Allergy Clin.Immunol. 108:430-438). Recent studies have suggested that IL-17F plays arole in the induction of inflammatory responses (Oda et al., 2006,American J. Resp. Crit. Care Medicine, Jan. 15, 2006; Numasaki et al.,2004, Immunol Lett. 95:97-104).

Aspects of the invention provide antigen binding proteins thatspecifically bind IL-17RA and inhibit IL-17RA activation mediated byIL-17 family members, such as, but not limited to, IL-17A and/or IL-17F,as described more fully herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a phylogenetic dentogram analysis of the CDRs(complementarity determining regions) of the variable heavy (V_(H)) andvariable light (V_(L)) domains of various IL-17R antigen bindingproteins (antibodies).

FIG. 2 depicts an alignment of the amino acid sequences of the CDRs ofthe variable heavy (V_(H)) domains of various IL-17R antigen bindingproteins (antibodies). The CDR1, CDR2, and CDR3 regions are highlighted.

FIG. 3 depicts an alignment of the amino acid sequences of the CDRs ofthe variable light (V_(L)) domains of various IL-17R antigen bindingproteins (antibodies). The CDR1, CDR2, and CDR3 regions are highlighted.

FIG. 4 shows that the mean clinical scores of IL-17RA−/− mice (knockoutmice or KO mice) are much lower than that of wild-type (WT) mice in aCIA model of arthritis.

FIG. 5 shows the delay in experimental autoimmune encephalomyelitis(EAE) onset for IL-17RA knockout mice compared to wild-type mice in amyelin oligodendrocyte glycoprotein (MOG)-induced model.

FIG. 6 shows reduced clinical scores in IL-17RA knockout mice ascompared to wild-type mice in a MOG-induced model.

FIG. 7 shows IL-17RA knockout mice have reduced total numbers ofinflammatory cells in BAL fluid compared to wild-type in anovalbumin-induced model of asthma.

FIG. 8 shows IL-17RA knockout mice have reduced numbers of eosinophils(FIG. 8A), neutrophils (FIG. 8B) and lymphocytes (FIG. 8C) inbronchioalveolar lavage (BAL) fluid as compared to wild-type mice in anovalbumin-induced model of asthma. FIG. 8D shows no changes in BAL fluidmacrophage observed in either WT or IL-17RA knockout mice (naïve and OVAchallenged).

FIG. 9 shows dose-dependent inhibition by an IL-17RA mAb in a wild-type(WT) collagen-induced arthritis (CIA) model. A P<0.05 was seen whencomparing IL-17RA mAb at 100 μg and 300 μg treatment groups versuscontrol treatment group (days 13, 15 and 16).

FIG. 10 shows the results of therapeutic treatment with IL-17RA mAb. Thedata shows stabilized mean clinical scores in wild-type mice in astandard CIA model of arthritis. These data demonstrate that IL-17RAinhibition by an IL-17RA antigen binding protein may be therapeuticallyuseful in treating rheumatoid arthritis (RA), especially in thepreservation of joint bone and cartilage.

FIG. 11 shows that therapeutic treatment with anti-IL-17RA mAbstabilized mean clinical scores in TNFR p55/p75 knockout mice in astandard CIA model of arthritis. These data show that IL-17RA inhibitionby an IL-17RA antigen binding protein may be therapeutically useful intreating RA, especially in the preservation of joint bone and cartilage.Notably, IL-17RA inhibition was able to stabilize disease in a modelindependent of TNF signaling.

FIG. 12 shows exemplary IL-17RA human mAbs (AM_(H)14/AM_(L)14,AM_(H)22/AM_(L)22, AM_(H)19/AM_(L)19, and AM_(H)18/AM_(L)18) were ableto inhibit cynomologous IL-17-induced IL-6 production from JTC-12 cells(cynomologous kidney cell line). The (----) line depicts the positivecontrol value of cynomologous IL-17 in combination with TNF-alpha. The(-.-.-) line depicts the positive control value of cynomologousTNF-alpha. The ( . . . . ) line depicts the media control value.

FIG. 13 shows sequence variation in the framework regions of SEQ IDNO:40 (AM_(L)14) in relation to germline residues and the effect on IC50values.

FIG. 14 shows that the two variants having residues returned to germline(see FIG. 13) had reduced IL-17A inhibitory activity in relation toAM_(H)14/AM_(L)14, indicating that some variation in the frameworkregions was tolerated but that some residues may influence activity. The(----) line indicates the positive control value of IL-17 stimulation inthe absence of antibody (approximately 4062 pg/ml).

FIG. 15 shows that the two variants having residues returned to germline(see FIG. 13) had reduced IL-17F (in combination with TNF-alpha)inhibitory activity in relation to AM_(H)14/AM_(L)14.

FIGS. 16A and 16B show the results of multiplexed binding of IL-17RAantibodies. Shaded values indicate antibody pairs that can bind toIL-17RA simultaneously, suggesting that these antibodies bind todifferent neutralizing determinants. Boxed values indicate antibodiespaired against themselves.

FIG. 17 shows mouse IL-17RA (SEQ ID NO:432) and the 5 domains, A, B, C,D, E, and F that replaced the counterpart domains in the human IL-17RAsequence.

FIGS. 18A-18D shows the amino acid sequences for human and mouse IL-17RAand human/mouse chimeric IL-17RA proteins.

FIG. 19 is a table summarizing the IL-17RA mAbs capacity to bind thevarious chimeric proteins. Shaded values denote where the IL-17RA mAbslost binding to that particular chimera (n.d. means not determined).

FIG. 20 depicts the amino acid residues that were replaced with anarginine residue in SEQ ID NO:431.

FIG. 21 illustrates titration curves of various IL-17RA mAbs binding tothe D152R IL-17RA mutant.

FIG. 22 is a summary of the arginine scan, binding, and chimera data forvarious IL-17RA mAbs.

DETAILED DESCRIPTION OF THE INVENTION

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Standard techniques may be used for recombinant DNA, oligonucleotidesynthesis, tissue culture and transformation, protein purification etc.Enzymatic reactions and purification techniques may be performedaccording to the manufacturer's specifications or as commonlyaccomplished in the art or as described herein. The following proceduresand techniques may be generally performed according to conventionalmethods well known in the art and as described in various general andmore specific references that are cited and discussed throughout thespecification. See, e.g., Sambrook et al., 2001, Molecular Cloning: ALaboratory Manual, 3^(rd) ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., which is incorporated herein by reference for anypurpose. Unless specific definitions are provided, the nomenclature usedin connection with, and the laboratory procedures and techniques of,analytical chemistry, organic chemistry, and medicinal andpharmaceutical chemistry described herein are those well known andcommonly used in the art. Standard techniques may be used for chemicalsynthesis, chemical analyses, pharmaceutical preparation, formulation,and delivery and treatment of patients.

IL-17A, IL-17F, and IL-17RA

The biologic activities of IL-17A and IL-17F are dependent upon IL-17RA,as shown herein using both cells and mice that are genetically deficientin IL-17RA and with neutralizing mAbs (monoclonal antibodies) directedagainst IL-17RA (see Examples below).

“IL-17 receptor A” or “IL-17RA” (interchangeably used herein, as well asIL-17 receptor and IL-17R to refer to the same receptor) as used hereinis meant the cell surface receptor and receptor complexes (such as butnot limited to IL-17RA-IL-17RC complex), that bind IL-17A and IL-17F andas a result initiates a signal transduction pathway within the cell.IL-17RA proteins may also include variants. IL-17RA proteins may alsoinclude fragments, such as the extracellular domain that don't have allor part of the transmembrane and/or the intracellular domain, as well asfragments of the extracellular domain. The cloning, characterization,and preparation of IL-17RA are described, for example, in U.S. Pat. No.6,072,033, which is incorporated herein by reference in its entirety.The amino acid sequence of the human IL-17RA is shown in SEQ ID NO:430.Soluble forms of huIL-17RA useful in the methods of the presentinvention include the extracellular domain or the mature form lackingthe signal peptide or a fragment of the extracellular domain thatretains the capacity to bind IL-17A and/or IL-17F, or a heteromericversion of IL-17A and/or IL-17F. Other forms of IL-17RA include muteinsand variants that are at least between 70% and 99% homologous to thenative IL-17RA of SEQ ID NO:430 and as described in U.S. Pat. No.6,072,033, so long as the IL-17RA retains the capacity to bind IL-17Aand/or IL-17F, or a heteromeric version of IL-17A and/or IL-17F. Theterm “IL-17RA” also includes post-translational modifications of theIL-17RA amino acid sequence. Post-translational modifications include,but is not limited to, N- and O-linked glycosylation.

IL-17RA Antigen Binding Proteins

The present invention provides antigen binding proteins thatspecifically bind IL-17RA. Embodiments of antigen binding proteinscomprise peptides and/or polypeptides (that optionally includepost-translational modifications) that specifically bind IL-17RA.Embodiments of antigen binding proteins comprise antibodies andfragments thereof, as variously defined herein, that specifically bindIL-17RA. Aspects of the invention include antibodies that specificallybind to human IL-17RA and inhibit IL-17A and/or IL-17F from binding andactivating IL-17RA, or a heteromeric complex of IL-17RA and IL-17RC.Aspects of the invention include antibodies that specifically bind tohuman IL-17RA and inhibit an IL-17A/IL-17F heteromer from binding andactivating IL-17RA, or a heteromeric complex of IL-17RA and IL-17RC.Throughout the specification, when reference is made to inhibitingIL-17A and/or IL-17F, it is understood that this also includesinhibiting heteromers of IL-17A and IL-17F. Aspects of the inventioninclude antibodies that specifically bind to human IL-17RA and partiallyor fully inhibit IL-17RA from forming either a homomeric or heteromericfunctional receptor complex, such as, but not limited to, anIL-17RA-IL-17RC complex. Aspects of the invention include antibodiesthat specifically bind to human IL-17RA and partially or fully inhibitIL-17RA from forming either a homomeric or heteromeric functionalreceptor complex, such as, but not limited to IL-17RA/IL-17RC complexand do not necessarily inhibit IL-17A and/or IL-17F or an IL-17A/IL-17Fheteromer from binding to IL-17RA or a IL-17RA heteromeric receptorcomplex.

The antigen binding proteins of the invention specifically bind toIL-17RA. “Specifically binds” as used herein means that the antigenbinding protein preferentially binds IL-17RA over other proteins. Insome embodiments “specifically binds” means that the IL-17RA antigenbinding proteins have a higher affinity for IL-17RA than for otherproteins. For example, the equilibrium dissociation constant is <10⁻⁷ to10⁻¹¹ M, or <10⁻⁸ to <10⁻¹⁰ M, or <10⁻⁹ to <10⁻¹⁰ M.

It is understood that when reference is made to the various embodimentsof the IL-17RA antibodies described herein, that it also encompassesIL-17RA-binding fragments thereof. An IL-17RA-binding fragment comprisesany of the antibody fragments or domains described herein that retainsthe ability to specifically bind to IL-17RA. Said IL-17RA-bindingfragments may be in any of the scaffolds described herein. SaidIL-17RA-binding fragments also have the capacity to inhibit activationof the IL-17RA, as described throughout the specification.

In embodiments where the IL-17RA antigen binding protein is used fortherapeutic applications, one characteristic of an IL-17RA antigenbinding protein is that it can inhibit binding of IL-17A and/or IL-17Fto IL-17RA and one or more biological activities of, or mediated by,IL-17RA. Such antibodies are considered neutralizing antibodies becauseof their capacity to inhibit IL-17A and/or IL-17F from binding andcausing IL-17RA signaling and/or biological activity. In this case, anantigen binding protein specifically binds IL-17RA and inhibits bindingof IL-17A and/or IL-17F to IL-17RA from anywhere between 10 to 100%,such as by at least about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% or more (forexample by measuring binding in an in vitro competitive binding assay asdescribed herein). For example, IL-17RA antibodies may be tested forneutralizing ability by testing them for the production of IL-6 in humanforeskin fibroblast (HFF) assay (see for example Examples 8 and 9), orany suitable assay known in the art. Examples, for illustrative purposesonly, of additional biological activity of IL-17RA (e.g., assayreadouts) to test for inhibition of IL-17RA signaling and/or biologicalactivity include in vitro and/or in vivo measurement of one or more ofIL-8, CXCL1, CXCL2, GM-CSF, G-CSF, M-CSF, IL-1β, TNFα, RANK-L, LIF,PGE2, IL-12, MMPs (such as but not limited to MMP3 and MMP9), GROα, NO,and/or C-telopeptide and the like.

Embodiments of antigen binding proteins comprise a scaffold structure,as variously define herein, with one or more complementarity determiningregions (CDRs). Embodiments of antigen binding proteins comprise ascaffold structure with one or more variable domains, either heavy orlight. Embodiments include antibodies that comprise a light chainvariable region selected from the group consisting of AM_(L)1 throughAM_(L)26 (SEQ ID NO:27-53, respectively, with AM_(L)23 having twoversions—SEQ ID NOs:49 and 50) and/or a heavy chain variable regionselected from the group consisting of AM_(H)1 through AM_(H)26 (SEQ IDNO:1-26, respectively), and fragments, derivatives, muteins, andvariants thereof.

Additional examples of scaffolds that are envisioned include:fibronectin, neocarzinostatin CBM4-2, lipocalins, T-cell receptor,protein-A domain (protein Z), Im9, TPR proteins, zinc finger domains,pVIII, avian pancreatic polypeptide, GCN4, WW domain, Src homologydomain 3, PDZ domains, TEM-1 Beta-lactamase, thioredoxin, staphylococcalnuclease, PHD-finger domains, CL-2, BPTI, APPI, HPSTI, ecotin, LACI-D1,LDTI, MTI-II, scorpion toxins, insect defensin-A peptide, EETI-II,Min-23, CBD, PBP, cytochrome b-562, Ldl receptor domains,gamma-crystallin, ubiquitin, transferring, and/or C-type lectin-likedomains.

Aspects of the invention include antibodies comprising the followingvariable domains: AM_(L)1/AM_(H)1 (SEQ ID NO:27/SEQ ID NO:1),AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2), AM_(L)3/AM_(H)3 (SEQ IDNO:29/SEQ ID NO:3), AM_(L)4/AM_(H)4 (SEQ ID NO:30/SEQ ID NO:4),AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5), AM_(L)6/AM_(H)6 (SEQ IDNO:32/SEQ ID NO:6), AM_(L)7/AM_(H)7 (SEQ ID NO:33/SEQ ID NO:7),AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8), AM_(L)9/AM_(H)9 (SEQ IDNO:35/SEQ ID NO:9), AM_(L)10/AM_(H)10 (SEQ ID NO:36/SEQ ID NO:10),AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11), AM_(L)12/AM_(H)12 (SEQ IDNO:38/SEQ ID NO:12), AM_(L)13/AM_(H)13 (SEQ ID NO:39/SEQ ID NO:13),AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14), AM_(L)15/AM_(H)15 (SEQ IDNO:41/SEQ ID NO:15), AM_(L)16/AM_(H)16 (SEQ ID NO:42/SEQ ID NO:16),AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17), AM_(L)18/AM_(H)18 (SEQ IDNO:44/SEQ ID NO:18), AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19),AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20), AM_(L)21/AM_(H)21 (SEQ IDNO:47/SEQ ID NO:21), AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22),AM_(L)23/AM_(H)23 (SEQ ID NO:49 or SEQ ID NO:50/SEQ ID NO:23),AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24), AM_(L)25/AM_(H)25 (SEQ IDNO:52/SEQ ID NO:25), AM_(L)26/AM_(H)26 (SEQ ID NO:53/SEQ ID NO:26), andcombinations thereof, as well as and fragments, derivatives, muteins,and variants thereof.

In a further embodiment, a first amino acid sequence comprises CDR3,CDR2, and CDR1, and a second amino acid sequence comprises a CDR3, CDR2,and CDR1 of TABLE 1.

In another embodiment, the antigen binding protein comprises: A) a heavychain amino acid sequence that comprises at least one H-CDR1, H-CDR2, orH-CDR3 of a sequence selected from the group consisting of SEQ IDNO:1-26; and/or B) a light chain amino acid sequence that comprises atleast one L-CDR1, L-CDR2, or L-CDR3 of a sequence selected from thegroup consisting of SEQ ID NO:27-53.

In a further variation, the antigen binding protein comprises A) a heavychain amino acid sequence that comprises a H-CDR1, a H-CDR2, and aH-CDR3 of any of SEQ ID NO:1-26, and B) a light chain amino acidsequence that comprises a L-CDR1, a L-CDR2, and a L-CDR3 of any of SEQID NO:27-53. In another variation, the antigen binding protein comprisesan amino acid sequence that is of at least 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to a heavy chain amino acid sequence selected from the groupconsisting of SEQ ID NO:1-26 or a light chain amino acid sequenceselected from the group consisting of SEQ ID NO:27-53.

In certain embodiments, the CDRs include no more than one, two, three,four, five, or six amino acid additions, deletions, or substitutionsfrom a H-CDR1 (i.e., CDR1 of the heavy chain, etc.), H-CDR2, H-CDR3,L-CDR1 (i.e., CDR1 of the light chain, etc.), L-CDR2, and L-CDR3, andfragments, derivatives, muteins, and variants thereof.

Aspects of the invention include antibodies comprising a heavy chainvariable region selected from the group consisting of SEQ ID NO:1-26.Aspects of the invention include antibodies comprising a light chainvariable region selected from the group consisting of SEQ ID NO:27-53.Aspects of the invention include antibodies comprising a heavy chainvariable region selected from the group consisting of SEQ ID NO:1-26having no more than one, two, three, four, five, or six amino acidadditions, deletions, or substitutions. Aspects of the invention includeantibodies comprising a light chain variable region selected from thegroup consisting of SEQ ID NO:27-53 having no more than one, two, three,four, five, or six amino acid additions, deletions, or substitutions.Aspects of the invention include antibodies comprising a heavy chainvariable region selected from the group consisting of SEQ ID NO:1-26having no more than one, two, three, four, five, or six amino acidadditions, deletions, or substitutions and a light chain variable regionselected from the group consisting of SEQ ID NO:27-53 having no morethan one, two, three, four, five, or six amino acid additions,deletions, or substitutions.

In other embodiments, the heavy and light chain variable domains of theantigen binding proteins are defined by having a certain percentidentity to a reference heavy and/or light chain variable domain. Forexample, the antigen binding protein comprises A) a heavy chain variabledomain amino acid that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to a heavy chain amino acid sequence selected from the groupconsisting of SEQ ID NO:1-26; and B) a light chain variable domain aminoacid that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a lightchain amino acid sequence selected from the group consisting of SEQ IDNOs:27-53.

Aspects of the invention include a variety of embodiments including, butnot limited to, the following exemplary embodiments: Embodiment 1: anisolated antibody, comprising a monoclonal antibody or IL-17 receptor Abinding fragment thereof that is not fully murine and that specificallybinds IL-17 receptor A and inhibits IL-17A from binding and activatingsaid receptor. Embodiment 2: the antibody of embodiment 1, wherein saidantibody further inhibits IL-17F from binding and activating saidreceptor. Embodiment 3: the antibody of embodiment 1, wherein saidantibody is selected from the group consisting of: a. a humanizedantibody; b. a chimeric antibody; c. a recombinant antibody; d. a singlechain antibody; e. a diabody; f. a triabody; g. a tetrabody; h. a Fabfragment; i. a F(ab′)2 fragment; j. an IgD antibody; k. an IgE antibody;l. an IgM antibody; m. an IgG1 antibody; n. an IgG2 antibody; o. an IgG3antibody; and p. an IgG4 antibody.

Embodiment 4: the antibody of embodiment 3, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence of        AM_(L)1-26 (SEQ ID NOs:27-53, respectively);    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of        AM_(H)1-26 (SEQ ID NOs:1-26, respectively); or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b); and

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26;        wherein said antibody specifically binds IL-17 receptor A.

Embodiment 5: the antibody of embodiment 4, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

-   -   a. a light chain variable domain and a heavy chain variable        domain of AM_(L)1/AM_(H)1 (SEQ ID NO:27/SEQ ID NO:1);    -   b. a light chain variable domain and a heavy chain variable        domain of AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3);    -   d. a light chain variable domain and a heavy chain variable        domain of AM_(L)4/AM_(H)4 (SEQ ID NO:30/SEQ ID NO:4);    -   e. a light chain variable domain and a heavy chain variable        domain of AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5);    -   f. a light chain variable domain and a heavy chain variable        domain of AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6)    -   g. a light chain variable domain and a heavy chain variable        domain of AM_(L)7/AM_(H)7 (SEQ ID NO:33/SEQ ID NO:7);    -   h. a light chain variable domain and a heavy chain variable        domain of AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8);    -   i. a light chain variable domain and a heavy chain variable        domain of AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9);    -   j. a light chain variable domain and a heavy chain variable        domain of AM_(L)10/AM_(H)10 (SEQ ID NO:36/SEQ ID NO:10);    -   k. a light chain variable domain and a heavy chain variable        domain of AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11);    -   l. a light chain variable domain and a heavy chain variable        domain of AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12);    -   m. a light chain variable domain and a heavy chain variable        domain of AM_(L)13/AM_(H)13 (SEQ ID NO:39/SEQ ID NO:13);    -   n. a light chain variable domain and a heavy chain variable        domain of AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14);    -   o. a light chain variable domain and a heavy chain variable        domain of AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15);    -   p. a light chain variable domain and a heavy chain variable        domain of AM_(L)16/AM_(H)16 (SEQ ID NO:42/SEQ ID NO:16);    -   q. a light chain variable domain and a heavy chain variable        domain of AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17);    -   r. a light chain variable domain and a heavy chain variable        domain of AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18);    -   s. a light chain variable domain and a heavy chain variable        domain of AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19);    -   t. a light chain variable domain and a heavy chain variable        domain of AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20);    -   u. a light chain variable domain and a heavy chain variable        domain of AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21);    -   v. a light chain variable domain and a heavy chain variable        domain of AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22);    -   w. a light chain variable domain and a heavy chain variable        domain of AM_(L)23/AM_(H)23 (SEQ ID NO: 49 or SEQ ID NO:50/SEQ        ID NO:23);    -   x. a light chain variable domain and a heavy chain variable        domain of AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24);    -   y. a light chain variable domain and a heavy chain variable        domain of AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25); and    -   z. a light chain variable domain and a heavy chain variable        domain of AM_(L)26/AM_(H)26 (SEQ ID NO:53/SEQ ID NO:26); wherein        said antibody specifically binds IL-17 receptor A.

Embodiment 6: the antibody of embodiment 4, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26;        wherein said antibody specifically binds IL-17 receptor A.

Embodiment 7: the antibody of embodiment 2, wherein said antibody isselected from the group consisting of: a. a humanized antibody; b. achimeric antibody; c. a recombinant antibody; d. a single chainantibody; e. a diabody; f. a triabody; g. a tetrabody; h. a Fabfragment; i. a F(ab′)2 fragment; j. an IgD antibody; k. an IgE antibody;l. an IgM antibody; m. an IgG1 antibody; n. an IgG2 antibody; o. an IgG3antibody; and p. an IgG4 antibody.

Embodiment 8: the antibody of embodiment 7, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence of AM_(L)14,        18, 19, and 22 (SEQ ID NOs: 40, 44, 45, and 48, respectively);    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of AM_(H)14,        18, 19, and 22 (SEQ ID NOs:14, 18, 19, and 22, respectively); or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b);

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences:

-   -   a. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   b. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   c. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19; or    -   d. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;        and

C.

-   -   a. a light chain variable domain and a heavy chain variable        domain of AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14);    -   b. a light chain variable domain and a heavy chain variable        domain of AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19); or    -   d. a light chain variable domain and a heavy chain variable        domain of AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22); wherein        said antibody specifically binds IL-17 receptor A.

Embodiment 9: an isolated antibody, or an IL-17 receptor A bindingfragment thereof, comprising

-   -   a. a heavy chain CDR1 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁YGIS (SEQ ID NO:453) wherein X₁ is selected from the            group consisting of R, S and G;    -   b. a heavy chain CDR2 comprising an amino acid sequence selected        from the group consisting of:        -   i. WISX₁YX₂GNTX₃YAQX₄X₅QG (SEQ ID NO:456) wherein X₁ is            selected from the group consisting of A, X₂ is selected from            the group consisting of N, S and K, X₃ is selected from the            group consisting of N and K, X₄ is selected from the group            consisting of K and N, and X₅ is selected from the group            consisting of L and F;    -   c. a heavy chain CDR3 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁QLX₂X₃DY (SEQ ID NO:459), wherein X₁ is selected from            the group consisting of R and K, X₂ is selected from the            group consisting of Y, V, and A, and X₃ is selected from the            group consisting of F and L;        -   ii. X₁QLX₂FDY (SEQ ID NO:460), wherein X₁ is selected from            the group consisting of R and K, and X₂ is selected from the            group consisting of Y and V;    -   d. a light chain CDR1 comprising an amino acid sequence selected        from the group consisting of:        -   i. RASQSX₁X₂X₃X₄LA (SEQ ID NO:462), wherein X₁ is selected            from the group consisting of V and I, X₂ is selected from            the group consisting of I and S, X₃ is selected from the            group consisting of S and T, X₄ is selected from the group            consisting of N and S, and X₅ is selected from the group            consisting of A and N, and        -   ii. RASQSX₁SSNLA (SEQ ID NO:471), wherein X₁ is selected            from the group consisting of V and I;    -   e. a light chain CDR2 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁X₂STRAX₃ (SEQ ID NO:466), wherein X₁ is selected from            the group consisting of G and D, X₂ is selected from the            group consisting of A and T, and X₃ is selected from the            group consisting of T and A, and        -   ii. X₁ASTRAX₂ (SEQ ID NO:472), wherein X₁ is selected from            the group consisting of G and D, and X₂ is selected from the            group consisting of A and T; and    -   f. a light chain CDR3 comprising an amino acid sequence selected        from the group consisting of:        -   i. QQYDX₁WPLT (SEQ ID NO:469), wherein X₁ is selected from            the group consisting of N, T, and I; wherein said antibody            specifically binds IL-17 receptor A.

Embodiment 10: the antibody of embodiment 9, wherein said antibodycomprises:

-   -   a. a heavy chain CDR1 amino acid sequence comprising X₁YGIS (SEQ        ID NO:453), wherein X₁ is selected from the group consisting of        R, S and G;    -   b. a heavy chain CDR2 amino acid sequence comprising        WISX₁YX₂GNTX₃YAQX₄X₅QG (SEQ ID NO:456), wherein X₁ is selected        from the group consisting of A, X₂ is selected from the group        consisting of N, S and K, X₃ is selected from the group        consisting of N and K, X₄ is selected from the group consisting        of K and N, and X₅ is selected from the group consisting of L        and F;    -   c. a heavy chain CDR3 amino acid sequence comprising X₁QLX₂FDY        (SEQ ID NO:460), wherein X₁ is selected from the group        consisting of R and K, and X₂ is selected from the group        consisting of Y and V;    -   d. a light chain CDR1 amino acid sequence comprising        RASQSX₁SSNLA (SEQ ID NO:471), wherein X₁ is selected from the        group consisting of V and I;    -   e. a light chain CDR2 amino acid sequence comprising X₁ASTRAX₂        (SEQ ID NO:472), wherein X₁ is selected from the group        consisting of G and D, and X₂ is selected from the group        consisting of A and T; and    -   f. a light chain CDR3 amino acid sequence comprising QQYDX₁WPLT        (SEQ ID NO:469), wherein X₁ is selected from the group        consisting of N, T, and I; wherein said antibody specifically        binds IL-17 receptor A.

Embodiment 1: the antibody of embodiment 9, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence of AM_(L)12,        14, 16, 17, 19, and 22 (SEQ ID NOs:38, 40, 42, 43, 45, and 48        respectively);    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of AM_(H)12,        14, 16, 17, 19, and 22 (SEQ ID NOs:12, 14, 16, 17, 19, and 22,        respectively); or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b);

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences:

-   -   a. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   b. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   c. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   d. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   e. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19; or    -   f. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;        and

C.

-   -   a. a light chain variable domain and a heavy chain variable        domain of AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12);    -   b. a light chain variable domain and a heavy chain variable        domain of AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)16/AM_(H)16 (SEQ ID NO:42/SEQ ID NO:16);    -   d. a light chain variable domain and a heavy chain variable        domain of AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17);    -   e. a light chain variable domain and a heavy chain variable        domain of AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22); wherein        said antibody specifically binds IL-17 receptor A.

Embodiment 12: a pharmaceutical composition, comprising the antibody ofembodiment 4. Embodiment 14: the antibody of embodiment 4, wherein saidantibody is a derivative of said antibody.

Embodiment 15: a polypeptide, comprising an amino acid sequence selectedfrom the group consisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence of        AM_(L)1-26 (SEQ ID NOs:27-53, respectively);    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of        AM_(H)1-26 (SEQ ID NOs:1-26, respectively); or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b); and

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26;        wherein said polypeptide specifically binds IL-17 receptor A.

Embodiment 16: the polypeptide of embodiment 15, wherein saidpolypeptide comprises an amino acid is selected from the groupconsisting of:

-   -   a. a light chain variable domain and a heavy chain variable        domain of AM_(L)1/AM_(H)1 (SEQ ID NO:27/SEQ ID NO:1);    -   b. a light chain variable domain and a heavy chain variable        domain of AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3);    -   d. a light chain variable domain and a heavy chain variable        domain of AM_(L)4/AM_(H)4 (SEQ ID NO:30/SEQ ID NO:4);    -   e. a light chain variable domain and a heavy chain variable        domain of AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5);    -   f. a light chain variable domain and a heavy chain variable        domain of AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6)    -   g. a light chain variable domain and a heavy chain variable        domain of AM_(L)7/AM_(H)7 (SEQ ID NO:33/SEQ ID NO:7);    -   h. a light chain variable domain and a heavy chain variable        domain of AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8);    -   i. a light chain variable domain and a heavy chain variable        domain of AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9);    -   j. a light chain variable domain and a heavy chain variable        domain of AM_(L)10/AM_(H)10 (SEQ ID NO:36/SEQ ID NO:10);    -   k. a light chain variable domain and a heavy chain variable        domain of AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11);    -   l. a light chain variable domain and a heavy chain variable        domain of AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12);    -   m. a light chain variable domain and a heavy chain variable        domain of AM_(L)13/AM_(H)13 (SEQ ID NO:39/SEQ ID NO:13);    -   n. a light chain variable domain and a heavy chain variable        domain of AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14);    -   o. a light chain variable domain and a heavy chain variable        domain of AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15);    -   p. a light chain variable domain and a heavy chain variable        domain of AM_(L)16/AM_(H)16 (SEQ ID NO:42/SEQ ID NO:16);    -   q. a light chain variable domain and a heavy chain variable        domain of AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17);    -   r. a light chain variable domain and a heavy chain variable        domain of AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18);    -   s. a light chain variable domain and a heavy chain variable        domain of AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19);    -   t. a light chain variable domain and a heavy chain variable        domain of AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20);    -   u. a light chain variable domain and a heavy chain variable        domain of AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21);    -   v. a light chain variable domain and a heavy chain variable        domain of AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22);    -   w. a light chain variable domain and a heavy chain variable        domain of AM_(L)23/AM_(H)23 (SEQ ID NO: 49 or SEQ ID NO:50/SEQ        ID NO:23);    -   x. a light chain variable domain and a heavy chain variable        domain of AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24);    -   y. a light chain variable domain and a heavy chain variable        domain of AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25); and    -   z. a light chain variable domain and a heavy chain variable        domain of AM_(L)26/AM_(H)26 (SEQ ID NO:53/SEQ ID NO:26); wherein        said polypeptide specifically binds IL-17 receptor A.

Embodiment 17: the polypeptide of embodiment 15, wherein saidpolypeptide comprises an amino acid sequence selected from the groupconsisting of:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:1), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26;        wherein said polypeptide specifically binds IL-17 receptor A.

Embodiment 18: the polypeptide of embodiment 15, wherein saidpolypeptide is a pharmaceutical composition.

Embodiment 19: an isolated antibody, selected from the group consistingof:

-   -   a) an antibody consisting of a heavy chain sequence of SEQ ID        NO:427 and a light chain sequence of SEQ ID NO:429;    -   b) an antibody consisting essentially of a heavy chain sequence        of SEQ ID NO:427 and a light chain sequence of SEQ ID NO:429;    -   c) an antibody comprising a heavy chain sequence of SEQ ID NO:        427;    -   d) an antibody comprising a light chain sequence of SEQ ID        NO:429;    -   e) an antibody comprising a heavy chain sequence of SEQ ID NO:        427 and a light chain sequence of SEQ ID NO:429;    -   f) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain sequence of SEQ ID NO: 427;    -   g) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain sequence of SEQ ID NO:429;    -   h) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain sequence of SEQ ID NO:427 and a light        chain sequence of SEQ ID NO:429;    -   i) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain variable region sequence of SEQ ID        NO:14;    -   j) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain variable region sequence of SEQ ID        NO:40;    -   k) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain variable region sequence of SEQ ID        NO:40 and a heavy chain variable region sequence of SEQ ID        NO:14;    -   l) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain CDR1 of SEQ ID NO:146, a heavy chain        CDR2 of SEQ ID NO:147, a heavy chain CDR3 of SEQ ID NO:148, a        light chain CDR1 of SEQ ID NO:224, a light chain CDR2 of SEQ ID        NO:225, and a light chain CDR3 of SEQ ID NO:226; and    -   m) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain CDR3 of SEQ ID NO:148 and a light chain        CDR3 of SEQ ID NO:226.

Embodiment 20: the antibody of embodiment 19, wherein said antibody is apharmaceutical composition. Embodiment 21: the antibody of embodiment19, wherein said antibody is a derivative of said antibody.

Embodiment 22: the antibody of embodiment 7, wherein said antibodycomprises an amino acid sequence selected from the group consisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence SEQ ID NO:        40;    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of SEQ ID        NO:14; or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b);

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences: CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225), CDR3 (SEQ IDNO:226) and a heavy chain CDR1 (SEQ ID NO:146), CDR2 (SEQ ID NO:147),CDR3 (SEQ ID NO:148); and

C. a light chain variable domain of SEQ ID NO:40 and a heavy chainvariable domain SEQ ID NO:14;

wherein said antibody specifically binds IL-17 receptor A.

Embodiment 23: the polypeptide of embodiment 16, wherein saidpolypeptide comprises a light chain variable domain of SEQ ID NO:40 anda heavy chain variable domain SEQ ID NO:14, wherein said polypeptidespecifically binds IL-17 receptor A. Embodiment 24: the polypeptide ofembodiment 16, wherein said polypeptide comprises SEQ ID NO:427 and SEQID NO:429, wherein said polypeptide specifically binds IL-17 receptor A.Embodiment 25: the polypeptide of embodiment 24, wherein saidpolypeptide is a pharmaceutical composition.

As a general structure, the antigen binding proteins of the inventioncomprise (a) a scaffold, and (b) one or a plurality of CDRs. A“complementary determining region” or “CDR,” as used herein, refers to abinding protein region that constitutes the major surface contact pointsfor antigen binding. Embodiments of the invention include one or moreCDRs embedded in a scaffold structure of the antigen binding protein.The scaffold structure of the antigen binding proteins may be theframework of an antibody, or fragment or variant thereof, or may becompletely synthetic in nature. Examples of various scaffold structuresof the antigen binding proteins of the invention are further describedhereinbelow.

The antigen binding proteins of the invention include scaffold regionsand one or more CDRs. An antigen binding protein of the invention mayhave between one and six CDRs (as typically do naturally occurringantibodies), for example, one heavy chain CDR1 (“H-CDR1”), and/or oneheavy chain CDR2 (“H-CDR2”), and/or one heavy chain CDR3 (“H-CDR3”),and/or one light chain CDR1 (“L-CDR1”), and/or one light chain CDR2(“L-CDR2”), and/or one light chain CDR3 (“L-CDR3”).

The term “naturally occurring” as used throughout the specification inconnection with biological materials such as peptides, polypeptides,nucleic acids, host cells, and the like, refers to materials which arefound in nature. In naturally occurring antibodies, a H-CDR1 typicallycomprises about five (5) to about seven (7) amino acids, H-CDR2typically comprises about sixteen (16) to about nineteen (19) aminoacids, and H-CDR3 typically comprises about three (3) to about twentyfive (25) amino acids. L-CDR1 typically comprises about ten (10) toabout seventeen (17) amino acids, L-CDR2 typically comprises about seven(7) amino acids, and L-CDR3 typically comprises about seven (7) to aboutten (10) amino acids. Specific CDRs of the various antibodies of theinvention are provided in TABLE 1 and the Sequence Listing.

TABLE 1 Corresponding Polynucleotide Sequence Amino acid SEQ ID NYYWNSEQ ID  sequence of NO: 107 NO: 266 CDR 1 of AM_(H)1 Vh Amino acidSEQ ID DIYYSGSTNYNPS SEQ ID  sequence of NO: 108 LKS NO: 267 CDR 2 ofAM_(H)1 Vh Amino acid SEQ ID DGELANYYGSGS SEQ ID sequence of NO: 109YQFYYYYGMDV  NO: 268 CDR 3 of AM_(H)1 Vh Amino acid SEQ ID GYYWS SEQ ID sequence of NO: 110 NO: 269 CDR 1 of AM_(H)2 Vh Amino acid SEQ IDEINHSGRTNYNPS SEQ ID  sequence of NO: 111 LKS NO: 270 CDR 2 ofAM_(H)2 Vh Amino acid SEQ ID GPYYFDSSGYLYY SEQ ID  sequence of NO: 112YYGLDV NO: 271 CDR 3 of AM_(H)2 Vh Amino acid SEQ ID SYGMH SEQ ID sequence of NO: 113 NO: 272 CDR 1 of AM_(H)3 Vh Amino acid SEQ IDVIWYDGSNKHYA SEQ ID  sequence of NO: 114 DSVKG NO: 273 CDR 2 ofAM_(H)3 Vh Amino acid SEQ ID DTGVY SEQ ID  sequence of NO: 115 NO: 274CDR 3 of AM_(H)3 Vh Amino acid SEQ ID SYGMH SEQ ID  sequence of NO: 116NO: 275 CDR 1 of AM_(H)4 Vh Amino acid SEQ ID VIWYDGSNKHYA SEQ ID sequence of NO: 117 DSVKG NO: 276 CDR 2 of AM_(H)4 Vh Amino acid SEQ IDDTGVY SEQ ID  sequence of NO: 118 NO: 277 CDR 3 of AM_(H)4 Vh Amino acidSEQ ID SYYWS SEQ ID  sequence of NO: 119 NO: 278 CDR 1 of AM_(H)5 VhAmino acid SEQ ID RIYRSGNTIYNPSL SEQ ID  sequence of NO: 120 KS NO: 279CDR 2 of AM_(H)5 Vh Amino acid SEQ ID ENYSESSGLYYYY SEQ ID  sequence ofNO: 121 GMDV NO: 280 CDR 3 of AM_(H)5 Vh Amino acid SEQ ID RYGIS SEQ ID sequence of NO: 122 NO: 281 CDR 1 of AM_(H)6 Vh Amino acid SEQ IDWISAYNGNTNYA SEQ ID  sequence of NO: 123 QKLQG NO: 282 CDR 2 ofAM_(H)6 Vh Amino acid SEQ ID RDYDILTGYYNGF SEQ ID  sequence of NO: 124DP NO: 283 CDR 3 of AM_(H)6 Vh Amino acid SEQ ID RYGIS SEQ ID sequence of NO: 125 NO: 284 CDR 1 of AM_(H)7 Vh Amino acid SEQ IDWISAYNGNTNYA SEQ ID  sequence of NO: 126 QKLQG NO: 285 CDR 2 ofAM_(H)7 Vh Amino acid SEQ ID RDYDILTGYYNGF SEQ ID  sequence of NO: 127DP NO: 286 CDR 3 of AM_(H)7 Vh Amino acid SEQ ID GYGIS SEQ ID sequence of NO: 128 NO: 287 CDR 1 of AM_(H)8 Vh Amino acid SEQ IDWISAYNGNTNYA SEQ ID  sequence of NO: 129 QNLQG NO: 288 CDR 2 ofAM_(H)8 Vh Amino acid SEQ ID RDYDILTGYYNGF SEQ ID  sequence of NO: 130DP NO: 289 CDR 3 of AM_(H)8 Vh Amino acid SEQ ID RYGIS SEQ ID sequence of NO: 131 NO: 290 CDR 1 of AM_(H)9 Vh Amino acid SEQ IDWISAYNGNTNYA SEQ ID  sequence of NO: 132 QKLQG NO: 291 CDR 2 ofAM_(H)9 Vh Amino acid SEQ ID RDYDILTGYYNGF SEQ ID  sequence of NO: 133DP NO: 292 CDR 3 of AM_(H)9 Vh Amino acid SEQ ID SGGYYWS SEQ ID sequence of NO: 134 NO: 293 CDR 1 of AM_(H)10 Vh Amino acid SEQ IDYIYFSGSAYYNPS SEQ ID  sequence of NO: 135 LKS NO: 294 CDR 2 ofAM_(H)10 Vh Amino acid SEQ ID EYYDSSGYPDAFD SEQ ID  sequence of NO: 136I NO: 295 CDR 3 of AM_(H)10 Vh Amino acid SEQ ID SYGMH SEQ ID sequence of NO: 137 NO: 296 CDR 1 of AM_(H)11 Vh Amino acid SEQ IDVIWYDGSNKYYA SEQ ID  sequence of NO: 138 DSVKG NO: 297 CDR 2 ofAM_(H)11 Vh Amino acid SEQ ID DTKDY SEQ ID  sequence of NO: 139 NO: 298CDR 3 of AM_(H)11 Vh Amino acid SEQ ID SYGIS SEQ ID  sequence of NO: 140NO: 299 CDR 1 of AM_(H)12 Vh Amino acid SEQ ID WISTYKGNTNYA SEQ ID sequence of NO: 141 QKLQG NO: 300 CDR 2 of AM_(H)12 Vh Amino acid SEQ IDKQLVFDY SEQ ID  sequence of NO: 142 NO: 301 CDR 3 of AM_(H)12 VhAmino acid SEQ ID SYGMQ SEQ ID  sequence of  NO: 143 NO: 302 CDR 1 ofAM_(H)13 Vh Amino acid SEQ ID VIWYDGNKKYYA SEQ ID  sequence of NO: 144DSVKG NO: 303 CDR 2 of AM_(H)13 Vh Amino acid SEQ ID GRVRDYYYGMD SEQ ID sequence of NO: 145 V NO: 304 CDR 3 of AM_(H)13 Vh Amino acid SEQ IDRYGIS SEQ ID  sequence of NO: 146 NO: 305 CDR 1 of AM_(H)14 VhAmino acid SEQ ID WISTYSGNTNYA SEQ ID  sequence of NO: 147 QKLQG NO: 306CDR 2 of AM_(H)14 Vh Amino acid SEQ ID RQLYFDY SEQ ID  sequence ofNO: 148 NO: 307 CDR 3 of AM_(H)14 Vh Amino acid SEQ ID SYGMQ SEQ ID sequence of NO: 149 NO: 308 CDR 1 of AM_(H)15 Vh Amino acid SEQ IDVIWYDGNKKYYA SEQ ID  sequence of NO: 150 DSVKG NO: 309 CDR 2 ofAM_(H)15 Vh Amino acid SEQ ID GRVRDYYYGMD SEQ ID  sequence of NO: 151 VNO: 310 CDR 3 of AM_(H)15 Vh Amino acid SEQ ID SYGIS SEQ ID  sequence ofNO: 152 NO: 311 CDR 1 of AM_(H)16 Vh Amino acid SEQ ID WISAYNGNTKYASEQ ID  sequence of NO: 153 QKLQG NO: 312 CDR 2 of AM_(H)16 VhAmino acid SEQ ID KQLVFDY SEQ ID  sequence of NO: 154 NO: 313 CDR 3 ofAM_(H)16 Vh Amino acid SEQ ID SYGIS SEQ ID  sequence of NO: 155 NO: 314CDR 1 of AM_(H)17 Vh Amino acid SEQ ID WISAYSGNTKYA SEQ ID  sequence ofNO: 156 QKLQG NO: 315 CDR 2 of AM_(H)17 Vh Amino acid SEQ ID KQLVFDYSEQ ID  sequence of NO: 157 NO: 316 CDR 3 of AM_(H)17 Vh Amino acidSEQ ID DYYMH SEQ ID  sequence of NO: 158 NO: 317 CDR 1 of AM_(H)18 VhAmino acid SEQ ID WMHPNSGGTDLA SEQ ID  sequence of NO: 159 QRFQG NO: 318CDR 2 of AM_(H)18 Vh Amino acid SEQ ID GGYCSTLSCSFYW SEQ ID  sequence ofNO: 160 YFDL NO: 319 CDR 3 of AM_(H)18 Vh Amino acid SEQ ID SYGISSEQ ID  sequence of NO: 161 NO: 320 CDR 1 of AM_(H)19 Vh Amino acidSEQ ID WISAYSGNTKYA SEQ ID  sequence of NO: 162 QKFQG NO: 321 CDR 2 ofAM_(H)19 Vh Amino acid SEQ ID RQLALDY SEQ ID  sequence of NO: 163NO: 322 CDR 3 of AM_(H)19 Vh Amino acid SEQ ID SYSMN SEQ ID  sequence ofNO: 164 NO: 323 CDR 1 of AM_(H)20 Vh Amino acid SEQ ID FISARSSTIYYADSSEQ ID  sequence of NO: 165 VKG NO: 324 CDR 2 of AM_(H)20 Vh Amino acidSEQ ID PKVGGGMDV SEQ ID  sequence of NO: 166 NO: 325 CDR 3 ofAM_(H)20 Vh Amino acid SEQ ID SYSMN SEQ ID  sequence of NO: 167 NO: 326CDR 1 of AM_(H)21 Vh Amino acid SEQ ID IISSRSSIIHYADSV SEQ ID sequence of NO: 168 KG NO: 327 CDR 2 of AM_(H)21 Vh Amino acid SEQ IDPKVGGGMDV SEQ ID  sequence of NO: 169 NO: 328 CDR 3 of AM_(H)21 VhAmino acid SEQ ID RYGIS SEQ ID  sequence of NO: 170 NO: 329 CDR 1 ofAM_(H)22 Vh Amino acid SEQ ID WISAYSGNTNYA SEQ ID  sequence of NO: 171QKLQG NO: 330 CDR 2 of AM_(H)22 Vh Amino acid SEQ ID RQLYFDY SEQ ID sequence of NO: 172 NO: 331 CDR 3 of AM_(H)22 Vh Amino acid SEQ ID SYYWSSEQ ID  sequence of NO: 173 NO: 332 CDR 1 of AM_(H)23 Vh Amino acidSEQ ID RIYPSGRTNYNPS SEQ ID  sequence of NO: 174 LKS NO: 333 CDR 2 ofAM_(H)23 Vh Amino acid SEQ ID EAYELQLGLYYY SEQ ID  sequence of NO: 175YGMDV NO: 334 CDR 3 of AM_(H)23 Vh Amino acid SEQ ID SYYWS SEQ ID sequence of NO: 176 NO: 335 CDR 1 of AM_(H)24 Vh Amino acid SEQ IDRIYPSGRTNYNPS SEQ ID  sequence of NO: 177 LKS NO: 336 CDR 2 ofAM_(H)24 Vh Amino acid SEQ ID EAYELQLGLYYY SEQ ID  sequence of NO: 178YGMDV NO: 337 CDR 3 of AM_(H)24 Vh Amino acid SEQ ID SGGYYWS SEQ ID sequence of NO: 179 NO: 338 CDR 1 of AM_(H)25 Vh Amino acid SEQ IDYSGNTYYNPSLRS SEQ ID  sequence of NO: 180 NO: 339 CDR 2 of AM_(H)25 VhAmino acid SEQ ID EAGGNSAYYYGM SEQ ID  sequence of NO: 181 DV NO: 340CDR 3 of AM_(H)25 Vh Amino acid SEQ ID DYYMS SEQ ID  sequence of NO: 182NO: 341 CDR 1 of AM_(H)26 Vh Amino acid SEQ ID YISSSGSTIYYADS SEQ ID sequence of NO: 183 VKG NO: 342 CDR 2 of AM_(H)26 Vh Amino acid SEQ IDDRTYYFGSGSYEG SEQ ID  sequence of NO: 184 MDV NO: 343 CDR 3 ofAM_(H)26 Vh Amino acid SEQ ID RASQGIRNDLG SEQ ID  sequence of NO: 185NO: 345 CDR 1 of AM_(L)1 Vl Amino acid SEQ ID AASSLQS SEQ ID sequence of NO: 186 NO: 346 CDR 2 of AM_(L)1 Vl Amino acid SEQ IDLQHNSNPFT SEQ ID  sequence of NO: 187 NO: 347 CDR 3 of AM_(L)1 VlAmino acid SEQ ID RASQSVSRNLV SEQ ID  sequence of NO: 188 NO: 348CDR 1 of AM_(L)2 Vl Amino acid SEQ ID GASTRAN SEQ ID  sequence ofNO: 189 NO: 349 CDR 2 of AM_(L)2 Vl Amino acid SEQ ID QQYKSWRT SEQ ID sequence of NO: 190 NO: 350 CDR 3 of AM_(L)2 Vl Amino acid SEQ IDRASQSISSYLN SEQ ID  sequence of NO: 191 NO: 351 CDR 1 of AM_(L)3 VlAmino acid SEQ ID AASSLQS SEQ ID  sequence of NO: 192 NO: 352 CDR 2 ofAM_(L)3 Vl Amino acid SEQ ID QQSYSTPFT SEQ ID  sequence of NO: 193NO: 353 CDR 3 of AM_(L)3 Vl Amino acid SEQ ID RASQSVSRNLA SEQ ID sequence of NO: 194 NO: 354 CDR 1 of AM_(L)4 Vl Amino acid SEQ IDGASTRAT SEQ ID  sequence of NO: 195 NO: 355 CDR 2 of AM_(L)4 VlAmino acid SEQ ID QQYNNWPTWT SEQ ID  sequence of NO: 196 NO: 356CDR 3 of AM_(L)4 Vl Amino acid SEQ ID RASQGIRNDLG SEQ ID  sequence ofNO: 197 NO: 357 CDR 1 of AM_(L)5 Vl Amino acid SEQ ID AASSFQS SEQ ID sequence of NO: 198 NO: 358 CDR 2 of AM_(L)5 Vl Amino acid SEQ IDLQHNSYPPT SEQ ID  sequence of NO: 199 NO: 359 CDR 3 of AM_(L)5 VlAmino acid SEQ ID RASQGIRNDLG SEQ ID  sequence of NO: 200 NO: 360CDR 1 of AM_(L)6 Vl Amino acid SEQ ID AASSLQS SEQ ID  sequence ofNO: 201 NO: 361 CDR 2 of AM_(L)6 Vl Amino acid SEQ ID LQHKSYPLT SEQ ID sequence of NO: 202 NO: 362 CDR 3 of AM_(L)6 Vl Amino acid SEQ IDRASQGIRNDLG SEQ ID  sequence of NO: 203 NO: 363 CDR 1 of AM_(L)7 VlAmino acid SEQ ID AASSLQS SEQ ID  sequence of NO: 204 NO: 364 CDR 2 ofAM_(L)7 Vl Amino acid SEQ ID LQHKSYPLT SEQ ID  sequence of NO: 205NO: 365 CDR 3 of AM_(L)7 Vl Amino acid SEQ ID RASQGIRNDLG SEQ ID sequence of NO: 206 NO: 366 CDR 1 of AM_(L)8 Vl Amino acid SEQ IDAASSLQS SEQ ID  sequence of NO: 207 NO: 367 CDR 2 of AM_(L)8 VlAmino acid SEQ ID LQHKSYPLT SEQ ID  sequence of NO: 208 NO: 368 CDR 3 ofAM_(L)8 Vl Amino acid SEQ ID RASQGIRNDLG SEQ ID  sequence of NO: 209NO: 369 CDR 1 of AM_(L)9 Vl Amino acid SEQ ID AASSLQS SEQ ID sequence of NO: 210 NO: 370 CDR 2 of AM_(L)9 Vl Amino acid SEQ IDLQHKSYPLT SEQ ID  sequence of NO: 211 NO: 371 CDR 3 of AM_(L)9 VlAmino acid SEQ ID RASQGIRSWLA SEQ ID  sequence of NO: 212 NO: 372CDR 1 of AM_(L)10 Vl Amino acid SEQ ID AASSLQS SEQ ID  sequence ofNO: 213 NO: 373 CDR 2 of AM_(L)10 Vl Amino acid SEQ ID QQANNFPRT SEQ ID sequence of NO: 214 NO: 374 CDR 3 of AM_(L)10 Vl Amino acid SEQ IDRASQSVSSNLA SEQ ID  sequence of NO: 215 NO: 375 CDR 1 of AM_(L)11 VlAmino acid SEQ ID GASTRAA SEQ ID  sequence of NO: 216 NO: 376 CDR 2 ofAM_(L)11 Vl Amino acid SEQ ID QHYINWPKWT SEQ ID  sequence of NO: 217NO: 377 CDR 3 of AM_(L)11 Vl Amino acid SEQ ID RASQSISSSLA SEQ ID sequence of NO: 218 NO: 378 CDR 1 of AM_(L)12 Vl Amino acid SEQ IDGASTRAT SEQ ID  sequence of NO: 219 NO: 379 CDR 2 of AM_(L)12 VlAmino acid SEQ ID QQYDNWPLT SEQ ID  sequence of NO: 220 NO: 380 CDR 3 ofAM_(L)12 Vl Amino acid SEQ ID KSSQSLLHSDGKT SEQ ID  sequence of NO: 221YLY NO: 381 CDR 1 of AM_(L)13 Vl Amino acid SEQ ID EVSTRFS SEQ ID sequence of NO: 222 NO: 382 CDR 2 of AM_(L)13 Vl Amino acid SEQ IDMQSIQLPLT SEQ ID  sequence of NO: 223 NO: 383 CDR 3 of AM_(L)13 VlAmino acid SEQ ID RASQSVSSNLA SEQ ID  sequence of NO: 224 NO: 384CDR 1 of AM_(L)14 Vl Amino acid SEQ ID DASTRAT SEQ ID  sequence ofNO: 225 NO: 385 CDR 2 of AM_(L)14 Vl Amino acid SEQ ID QQYDNWPLT SEQ ID sequence of NO: 226 NO: 386 CDR 3 of AM_(L)14 Vl Amino acid SEQ IDRASQSVSSNLA SEQ ID  sequence of NO: 227 NO: 387 CDR 1 of AM_(L)15 VlAmino acid SEQ ID DASTRAA SEQ ID  sequence of NO: 228 NO: 388 CDR 2 ofAM_(L)15 Vl Amino acid SEQ ID QQYDNWPLT SEQ ID  sequence of NO: 229NO: 389 CDR 3 of AM_(L)15 Vl Amino acid SEQ ID RASQSISTSLA SEQ ID sequence of NO: 230 NO: 390 CDR 1 of AM_(L)16 Vl Amino acid SEQ IDGTSTRAT SEQ ID  sequence of NO: 231 NO: 391 CDR 2 of AM_(L)16 VlAmino acid SEQ ID QQYDIWPLT SEQ ID  sequence of NO: 232 NO: 392 CDR 3 ofAM_(L)16 Vl Amino acid SEQ ID RASQSVSSNLA SEQ ID  sequence of NO: 233NO: 393 CDR 1 of AM_(L)17 Vl Amino acid SEQ ID GASTRAT SEQ ID sequence of NO: 234 NO: 394 CDR 2 of AM_(L)17 Vl Amino acid SEQ IDQQYDNWPLT SEQ ID  sequence of NO: 235 NO: 395 CDR 3 of AM_(L)17 VlAmino acid SEQ ID KTSQSVLYSSKNK SEQ ID  sequence of NO: 236 NFLA NO: 396CDR 1 of AM_(L)18 Vl Amino acid SEQ ID WASTRES SEQ ID  sequence ofNO: 237 NO: 397 CDR 2 of AM_(L)18 Vl Amino acid SEQ ID QQYYSTPFT SEQ ID sequence of NO: 238 NO: 398 CDR 3 of AM_(L)18 Vl Amino acid SEQ IDRASQSISSNLA SEQ ID  sequence of NO: 239 NO: 399 CDR 1 of AM_(L)19 VlAmino acid SEQ ID GASTRAT SEQ ID  sequence of NO: 240 NO: 400 CDR 2 ofAM_(L)19 Vl Amino acid SEQ ID QQYDTWPLT SEQ ID  sequence of NO: 241NO: 401 CDR 3 of AM_(L)19 Vl Amino acid SEQ ID RASQGISNYLA SEQ ID sequence of NO: 242 NO: 402 CDR 1 of AM_(L)20 Vl Amino acid SEQ IDAASTLQS SEQ ID  sequence of NO: 243 NO: 403 CDR 2 of AM_(L)20 VlAmino acid SEQ ID QKYNRAPFT SEQ ID  sequence of NO: 244 NO: 404 CDR 3 ofAM_(L)20 Vl Amino acid SEQ ID RASQGISNYLA SEQ ID  sequence of NO: 245NO: 405 CDR 1 of AM_(L)21 Vl Amino acid SEQ ID AASTLQS SEQ ID sequence of NO: 246 NO: 406 CDR 2 of AM_(L)21 Vl Amino acid SEQ IDQKYNRAPFT SEQ ID  sequence of NO: 247 NO: 407 CDR 3 of AM_(L)21 VlAmino acid SEQ ID RASQSVSSNLA SEQ ID  sequence of NO: 248 NO: 408CDR 1 of AM_(L)22 Vl Amino acid SEQ ID DASTRAA SEQ ID  sequence ofNO: 249 NO: 409 CDR 2 of AM_(L)22 Vl Amino acid SEQ ID QQYDNWPLT SEQ ID sequence of NO: 250 NO: 410 CDR 3 of AM_(L)22 Vl Amino acid SEQ IDRASQGIINDLG SEQ ID  sequence of NO: 251 NO: 411 CDR 1 of AM_(L)23 Vlversion 1 Amino acid SEQ ID AASSLQS SEQ ID  sequence of NO: 252 NO: 412CDR 2 of AM_(L)23 Vl version 1 Amino acid SEQ ID LQHNSYPPT SEQ ID sequence of NO: 253 NO: 413 CDR 3 of AM_(L)23 Vl version 1 Amino acidSEQ ID RSSQSLVYSDGHT SEQ ID  sequence of NO: 254 CLN NO: 414 CDR 1 ofAM_(L)23 Vl version 2 Amino acid SEQ ID KVSNWDS SEQ ID  sequence ofNO: 255 NO: 415 CDR 2 of AM_(L)23 Vl version 2 Amino acid SEQ IDMQGTHWPLCS SEQ ID  sequence of NO: 256 NO: 416 CDR 3 of AM_(L)23 Vlversion 2 Amino acid SEQ ID RSSQSLVYSDGHT SEQ ID  sequence of NO: 257CLN NO: 417 CDR 1 of AM_(L)24 Vl Amino acid SEQ ID KVSNWDS SEQ ID sequence of NO: 258 NO: 418 CDR 2 of AM_(L)24 Vl Amino acid SEQ IDMQGTHWPLCS SEQ ID  sequence of NO: 259 NO: 419 CDR 3 of AM_(L)24 VlAmino acid SEQ ID RASQAISIYLA SEQ ID  sequence of NO: 260 NO: 420CDR 1 of AM_(L)25 Vl Amino acid SEQ ID AASSLQS SEQ ID  sequence ofNO: 261 NO: 421 CDR 2 of AM_(L)25 Vl Amino acid SEQ ID QQYSSYPRT SEQ ID sequence of NO: 262 NO: 422 CDR 3 of AM_(L)25 Vl Amino acid SEQ IDRASQSVYSNLA SEQ ID  sequence of NO: 263 NO: 423 CDR 1 of AM_(L)26 VlAmino acid SEQ ID GASTRAT SEQ ID  sequence of NO: 264 NO: 424 CDR 2 ofAM_(L)26 Vl Amino acid SEQ ID QQYYNWPWT SEQ ID  sequence of NO: 265NO: 425 CDR 3 of AM_(L)26 Vl

The general structure and properties of CDRs within naturally occurringantibodies have been described in the art. Briefly, in a traditionalantibody scaffold, the CDRs are embedded within a framework in the heavyand light chain variable region where they constitute the regionslargely responsible for antigen binding and recognition. A variableregion comprises at least three heavy or light chain CDRs, see, supra(Kabat et al., 1991, Sequences of Proteins of Immunological Interest,Public Health Service N.I.H., Bethesda, Md.; see also Chothia and Lesk,1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:877-883), within a framework region (designated framework regions 1-4,FR1, FR2, FR3, and FR4, by Kabat et al., 1991, supra; see also Chothiaand Lesk, 1987, supra). See, infra. The CDRs provided by the presentinvention, however, may not only be used to define the antigen bindingdomain of a traditional antibody structure, but may be embedded in avariety of other scaffold structures, as described herein.

Antibodies of the invention can comprise any constant region known inthe art. The light chain constant region can be, for example, a kappa-or lambda-type light chain constant region, e.g., a human kappa- orlambda-type light chain constant region. The heavy chain constant regioncan be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-typeheavy chain constant regions, e.g., a human alpha-, delta-, epsilon-,gamma-, or mu-type heavy chain constant region. In one embodiment, thelight or heavy chain constant region is a fragment, derivative, variant,or mutein of a naturally occurring constant region.

In another embodiment, the invention provides an antigen binding proteinthat specifically binds IL-17RA, wherein said antigen binding proteincomprises a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2,and CDR3 that differs by no more than a total of one, two, three, four,five, or six amino acid additions, substitutions, and/or deletions fromthe following CDR sequences:CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),CDR3 (SEQ ID NO:187) and heavy chain CDR1 (SEQ ID NO:107), CDR2 (SEQ IDNO:108), CDR3 (SEQ ID NO:109) of antibody AM-1; light chain CDR1 (SEQ IDNO:188), CDR2 (SEQ ID NO:189), CDR3 (SEQ ID NO:190) and heavy chain CDR1(SEQ ID NO:110), CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibodyAM-2; light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192), CDR3 (SEQID NO:193) and heavy chain CDR1 (SEQ ID NO:113), CDR2 (SEQ ID NO:114),CDR3 (SEQ ID NO:115) of antibody AM-3; light chain CDR1 (SEQ ID NO:194),CDR2 (SEQ ID NO:195), CDR3 (SEQ ID NO:196) and heavy chain CDR1 (SEQ IDNO:116), CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198), CDR3 (SEQ IDNO:199) and heavy chain CDR1 (SEQ ID NO:119), CDR2 (SEQ ID NO:120), CDR3(SEQ ID NO:121) of antibody AM-5; light chain CDR1 (SEQ ID NO:200), CDR2(SEQ ID NO:201), CDR3 (SEQ ID NO:202) and heavy chain CDR1 (SEQ IDNO:122), CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204), CDR3 (SEQ IDNO:205) and heavy chain CDR1 (SEQ ID NO:125), CDR2 (SEQ ID NO:126), CDR3(SEQ ID NO:127) of antibody AM-7; light chain CDR1 (SEQ ID NO:206), CDR2(SEQ ID NO:207), CDR3 (SEQ ID NO:208) and heavy chain CDR1 (SEQ IDNO:128), CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210), CDR3 (SEQ IDNO:211) and heavy chain CDR1 (SEQ ID NO:131), CDR2 (SEQ ID NO:132), CDR3(SEQ ID NO:133) of antibody AM-9; light chain CDR1 (SEQ ID NO:212), CDR2(SEQ ID NO:213), CDR3 (SEQ ID NO:214) and heavy chain CDR1 (SEQ IDNO:134), CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216), CDR3 (SEQ IDNO:217) and heavy chain CDR1 (SEQ ID NO:137), CDR2 (SEQ ID NO:138), CDR3(SEQ ID NO:139) of antibody AM-11; light chain CDR1 (SEQ ID NO:218),CDR2 (SEQ ID NO:219), CDR3 (SEQ ID NO:220) and heavy chain CDR1 (SEQ IDNO:140), CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222), CDR3 (SEQ IDNO:223) and heavy chain CDR1 (SEQ ID NO:143), CDR2 (SEQ ID NO:144), CDR3(SEQ ID NO:145) of antibody AM-13; light chain CDR1 (SEQ ID NO:224),CDR2 (SEQ ID NO:225), CDR3 (SEQ ID NO:226) and heavy chain CDR1 (SEQ IDNO:146), CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228), CDR3 (SEQ IDNO:229) and heavy chain CDR1 (SEQ ID NO:149), CDR2 (SEQ ID NO:150), CDR3(SEQ ID NO:151) of antibody AM-15; light chain CDR1 (SEQ ID NO:230),CDR2 (SEQ ID NO:231), CDR3 (SEQ ID NO:232) and heavy chain CDR1 (SEQ IDNO:152), CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234), CDR3 (SEQ IDNO:235) and heavy chain CDR1 (SEQ ID NO:155), CDR2 (SEQ ID NO:156), CDR3(SEQ ID NO:157) of antibody AM-17; light chain CDR1 (SEQ ID NO:236),CDR2 (SEQ ID NO:237), CDR3 (SEQ ID NO:238) and heavy chain CDR1 (SEQ IDNO:158), CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240), CDR3 (SEQ IDNO:241) and heavy chain CDR1 (SEQ ID NO:161), CDR2 (SEQ ID NO:162), CDR3(SEQ ID NO:163) of antibody AM-19; light chain CDR1 (SEQ ID NO:242),CDR2 (SEQ ID NO:243), CDR3 (SEQ ID NO:244) and heavy chain CDR1 (SEQ IDNO:164), CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246), CDR3 (SEQ IDNO:247) and heavy chain CDR1 (SEQ ID NO:167), CDR2 (SEQ ID NO:168), CDR3(SEQ ID NO:169) of antibody AM-21; light chain CDR1 (SEQ ID NO:248),CDR2 (SEQ ID NO:249), CDR3 (SEQ ID NO:250) and heavy chain CDR1 (SEQ IDNO:170), CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252), CDR3 (SEQ IDNO:253) and heavy chain CDR1 (SEQ ID NO:173), CDR2 (SEQ ID NO:174), CDR3(SEQ ID NO:175) of antibody AM-23; light chain CDR1 (SEQ ID NO:254),CDR2 (SEQ ID NO:255), CDR3 (SEQ ID NO:256) and heavy chain CDR1 (SEQ IDNO:173), CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258), CDR3 (SEQ IDNO:259) and heavy chain CDR1 (SEQ ID NO:176), CDR2 (SEQ ID NO:177), CDR3(SEQ ID NO:178) of antibody AM-24; light chain CDR1 (SEQ ID NO:260),CDR2 (SEQ ID NO:261), CDR3 (SEQ ID NO:262) and heavy chain CDR1 (SEQ IDNO:179), CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25;or light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264), CDR3 (SEQ IDNO:265) and heavy chain CDR1 (SEQ ID NO:182), CDR2 (SEQ ID NO:183), CDR3(SEQ ID NO:184) of antibody AM-26, and fragments, derivatives, muteins,and variants thereof.

The CDRs of the invention also include consensus sequences derived fromgroups of related monoclonal antibodies. The antibodies may be relatedby both sequence homology and function, as shown in the Examples. Asdescribed herein, a “consensus sequence” refers to amino acid sequenceshaving conserved amino acids common among a number of sequences andvariable amino acids that vary within given amino acid sequences. TheCDR consensus sequences of the invention include CDRs corresponding toeach of H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 and L-CDR3.

Consensus sequences were determined using standard phylogenic analysesof the CDRs corresponding to the VH (i.e., Variable Heavy, etc.) & VL ofanti-IL-17RA antibodies. Two different approaches were employed. In afirst approach, the consensus sequences were determined by keeping theCDRs contiguous within the same sequence corresponding to a VH or VL. Ina second approach, the consensus sequences were determined by aligningthe various types of CDRs, i.e., H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2and L-CDR3 sequences of the IL-17RA antigen binding proteins disclosedherein independently.

In the first approach, briefly, amino acid sequences corresponding tothe entire variable domains of either VH or VL were converted to FASTAformatting for ease in processing comparative alignments and inferringphylogenies. Next, framework regions of these sequences were replacedwith an artificial linker sequence (GGGAAAGGGAAA, SEQ ID NO:448) so thatexamination of the CDRs alone could be performed without introducing anyamino acid position weighting bias due to coincident events (e.g., suchas unrelated antibodies that serendipitously share a common germlineframework heritage) whilst still keeping CDRs contiguous within the samesequence corresponding to a VH or VL. VH or VL sequences of this formatwere then subjected to sequence similarity alignment interrogation usinga program that employs a standard ClutalW-like algorithm (see, Thompsonet al., 1994, Nucleic Acids Res. 22:4673-4680). A gap creation penaltyof 8.0 was employed along with a gap extension penalty of 2.0. Thisprogram likewise generated phylograms (phylogenic tree illustrations)based on sequence similarity alignments using either UPGMA (unweightedpair group method using arithmetic averages) or Neighbor-Joining methods(see, Saitou and Nei, 1987, Molecular Biology and Evolution 4:406-425)to construct & illustrate similarity and distinction of sequence groupsvia branch length comparison and grouping. Both methods produced similarresults but UPGMA-derived trees were ultimately used as the methodemploys a simpler and more conservative set of assumptions.UPGMA-derived trees are shown in FIG. 1 where similar groups ofsequences were defined as having fewer than 15 substitutions per 100residues (see legend in tree illustrations for scale) amongst individualsequences within the group and were used to define consensus sequencecollections. The original sequence alignments generated were employed toempirically examine and document the occurrence of amino acids toleratedat each position with a consensus group and are shown in FIGS. 2 and 3.Consensus sequences for the groups of similar sequences within each CDRwere then prepared. Amino acids that varied within each group were notedwith the notation X_(n) within each consensus sequence.

The H-CDR1 consensus sequences include amino acid sequences selectedfrom the group consisting of: a) X₁YGIS (SEQ ID NO:453), wherein X₁ isselected from the group consisting of R, S and G; b) X₁YX₂MX₃ (SEQ IDNO:454), wherein X₁ is selected from the group consisting of D and S; X₂is selected from the group consisting of Y and S; and X₃ is selectedfrom the group consisting of S and N; and c) SYGMX₁ (SEQ ID NO:455),wherein X₁ is selected from the group consisting of H and Q;

The H-CDR2 consensus sequences include amino acid sequence selected fromthe group consisting of: a) WISX₁YX₂GNTX₃YAQX₄X₅QG (SEQ ID NO:456),wherein X₁ is selected from the group consisting of A and T; X₂ isselected from the group consisting of N, S and K; X₃ is selected fromthe group consisting of N and K; X₄ is selected from the groupconsisting of K and N; and X₅ is selected from the group consisting of Land F; b) X₁X₂SX₃X₄X₁SX₆IX₇YADSVKG (SEQ ID NO:457), wherein X₁ isselected from the group consisting of Y, I and F; X₂ is selected fromthe group consisting of I and S; X₃ is selected from the groupconsisting of S and A; X₄ is selected from the group consisting of S andR; and X₅ is selected from the group consisting of G, S and no aminoacid; X₆ is selected from the group consisting of T and I; and X₇ isselected from the group consisting of Y and H; and c)VIWYDGX₁X₂KX₃YADSVKG (SEQ ID NO:458), wherein X₁ is selected from thegroup consisting of S and N; X₂ is selected from the group consisting ofN and K; and X₃ is selected from the group consisting of H and Y.

The H-CDR3 consensus sequences include amino acid sequence selected fromthe group consisting of: a) X₁QLX₂X₃DY (SEQ ID NO:459), wherein X₁ isselected from the group consisting of R and K, X₂ is selected from thegroup consisting of Y, V, and A, and X₃ is selected from the groupconsisting of F and L and b) X₁QLX₂FDY (SEQ ID NO:460), wherein X₁ isselected from the group consisting of R and K, and X₂ is selected fromthe group consisting of Y and V.

The L-CDR1 consensus sequence includes an amino acid sequence selectedfrom the group consisting of: a) RASQX₁IX₂X₃X₄LX₅ (SEQ ID NO:461),wherein X₁ is selected from the group consisting of G, S, and A; X₂ isselected from the group consisting of R and S; X₃ is selected from thegroup consisting of S, I and N; X₄ is selected from the group consistingof W and Y; and X₅ is selected from the group consisting of A and N; b)RASQSX₁X₂X₃X₄LA (SEQ ID NO:462), wherein X₁ is selected from the groupconsisting of V and I; X₂ is selected from the group consisting of I andS; X₃ is selected from the group consisting of S and T; X₄ is selectedfrom the group consisting of N and S; and X₅ is selected from the groupconsisting of A and N; and c) RASQSVX₁X₂NLX₃ (SEQ ID NO:463), wherein X₁is selected from the group consisting of Y and S; X₂ is selected fromthe group consisting of S and R; and X₃ is selected from the groupconsisting of A and V.

The L-CDR2 consensus sequence includes an amino acid sequence selectedfrom the group consisting of: a) AASSX₁QS (SEQ ID NO:464), wherein X₁ isselected from the group consisting of L and F; b) AASX₁LQS (SEQ IDNO:465), wherein X₁ is selected from the group consisting of S and T; c)X₁X₂STRAX₃ (SEQ ID NO:466), wherein X₁ is selected from the groupconsisting of G and D; X₂ is selected from the group consisting of A andT; and X₃ is selected from the group consisting of T and A; and d)GASTRAX₁ (SEQ ID NO:473), wherein X₁ is selected from the groupconsisting of A, T and N.

The L-CDR3 consensus sequences include amino acid sequences selectedfrom the group consisting of: a) LQHX₁SYX₂X₃T (SEQ ID NO:467), whereinX₁ is selected from the group consisting of K and N; X₂ is selected fromthe group consisting of P and N; and X₃ is selected from the groupconsisting of L, F and P; b) QX₁X₂X₃X₄X₅PX₆T (SEQ ID NO:468), wherein X₁is selected from the group consisting of Q and K; X₂ is selected fromthe group consisting of A, S and Y; X₃ is selected from the groupconsisting of N, Y and S; X₄ is selected from the group consisting of N,S and R; X₅ is selected from the group consisting of F, T, Y and A; andX₆ is selected from the group consisting of R and F; c) QQYDX₁WPLT (SEQID NO:469), wherein X₁ is selected from the group consisting of N, T andI; and d) QX₁YX₂X₃WX₄X₅X₆T (SEQ ID NO:470), wherein X₁ is selected fromthe group consisting of H and Q; X₂ is selected from the groupconsisting of I, Y, N and K; X₃ is selected from the group consisting ofN and S; X₄ is selected from the group consisting of P and R; X₅ isselected from the group consisting of K, no amino acid, and T; and X₆ isselected from the group consisting of W and no amino acid.

FIGS. 1, 2, 3, 16A, 16B, 19, and 22 show that a clear pattern in thedata exists between sequence homology in the CDR domains and theantibodies function, as determined by cross-competition binding and thedetermination of where the antibodies bound to IL-17RA. Thus, astructure/function relation for classes of antibodies has beenestablished for the IL-17RA antibodies provided herein.

In a second approach CDR consensus sequences were determined for eachseparate CDR, independently of their contiguous context within the samesequence corresponding to a VH or VL. In this approach the consensussequences were determined by aligning each H-CDR1, H-CDR2, H-CDR3,L-CDR1, L-CDR2, and L-CDR3 in groups, i.e., by aligning the individualH-CDR1 sequences of the IL-17RA antigen binding proteins disclosedherein to determine a H-CDR1 consensus sequence, by aligning theindividual H-CDR2 sequences of the IL-17RA antigen binding proteinsdisclosed herein to determine a H-CDR2 consensus sequence, by aligningthe individual H-CDR3 sequences of the IL-17RA antigen binding proteinsdisclosed herein to determine a H-CDR3 consensus sequence, by aligningthe individual L-CDR1 sequences of the IL-17RA antigen binding proteinsdisclosed herein to determine a L-CDR1 consensus sequence, by aligningthe individual L-CDR2 sequences of the IL-17RA antigen binding proteinsdisclosed herein to determine a L-CDR2 consensus sequence, and byaligning the individual L-CDR3 sequences of the IL-17RA antigen bindingproteins disclosed herein to determine a L-CDR3 consensus sequence.Similarities between sequences within each individual CDR sequences wereidentified. Consensus sequences for the groups of similar sequenceswithin each CDR were then prepared. Amino acids that varied within eachgroup were noted with the notation X_(n) within each consensus sequence.

In another embodiment, the invention provides an antigen binding proteinthat specifically binds IL-17RA, wherein said antigen binding proteincomprises at least one H-CDR region of any of SEQ ID NOs:107-184. Otherembodiments include antigen binding proteins that specifically bind toIL-17RA, wherein said antigen binding protein comprises at least oneL-CDR region of any of SEQ ID NOs:185-265. Other embodiments includeantigen binding proteins that specifically binds IL-17RA, wherein saidantigen binding protein comprises at least one H-CDR region of any ofSEQ ID NOs:107-184 and at least one L-CDR region of any of SEQ IDNOs:185-265.

In another embodiment, the invention provides an antigen binding proteinthat specifically binds IL-17RA, wherein said antigen binding proteincomprises at least two H-CDR regions of any of SEQ ID NOs:107-184. Otherembodiments include antigen binding proteins that specifically bind toIL-17RA, wherein said antigen binding protein comprises at least twoL-CDR region of any of SEQ ID NOs:185-265. Other embodiments includeantigen binding proteins that specifically binds IL-17RA, wherein saidantigen binding protein comprises at least two H-CDR region of any ofSEQ ID NOs:107-184 and at least two L-CDR region of any of SEQ IDNOs:185-265.

In another embodiment, the invention provides an antigen binding proteinthat specifically binds IL-17RA, wherein said antigen binding proteincomprises at least three H-CDR regions of any of SEQ ID NOs:107-184.Other embodiments include antigen binding proteins that specificallybind to IL-17RA, wherein said antigen binding protein comprises at leastthree L-CDR region of any of SEQ ID NOs:185-265. Other embodimentsinclude antigen binding proteins that specifically binds IL-17RA,wherein said antigen binding protein comprises at least three H-CDRregion of any of SEQ ID NOs:107-184 and at least three L-CDR region ofany of SEQ ID NOs:185-265.

In another embodiment, the invention provides an antigen binding proteinthat specifically binds IL-17RA, wherein said antigen binding proteincomprises at least one, two, or three H-CDR regions of any of SEQ IDNOs:107-184, wherein said H-CDR regions are at least 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% identical to the respective H-CDR. Other embodiments includeantigen binding proteins that specifically bind to IL-17RA, wherein saidantigen binding protein comprises at least one, two, or three L-CDRregion of any of SEQ ID NOs:185-265, wherein said L-CDR regions are atleast 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the respective L-CDR.Other embodiments include antigen binding proteins that specificallybinds IL-17RA, wherein said antigen binding protein comprises at leastone, two, or three H-CDR regions of any of SEQ ID NOs:107-184, whereinsaid H-CDR regions are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identicalto the respective H-CDR, and comprises at least one, two, or three L-CDRregion of any of SEQ ID NOs:185-265, wherein said L-CDR regions are atleast 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the respective L-CDR.

In another embodiment, the invention provides an antigen binding proteinthat binds IL-17RA, wherein said antigen binding protein comprises atleast one H-CDR region having no more than one, two, three, four, five,or six amino acid additions, deletions or substitutions of any of SEQ IDNOs:107-184 and/or at least one L-CDR region having no more than one,two, three, four, five, or six amino acid additions, deletions orsubstitutions of any of SEQ ID NOs:185-265.

In another embodiment, the invention provides an antigen binding proteinthat binds IL-17RA, wherein said antigen binding protein comprises one,two, or three H-CDR region having no more than one, two, three, four,five, or six amino acid additions, deletions or substitutions of any ofSEQ ID NOs:107-184 and/or one, two, or three L-CDR region having no morethan one, two, three, four, five, or six amino acid additions, deletionsor substitutions of any of SEQ ID NOs:185-265.

Additional embodiments utilize antigen binding proteins comprising oneCDR having no more than one, two, three, four, five, or six amino acidadditions, deletions or substitutions of the sequence selected from theH-CDR regions of any of SEQ ID NOs:107-184 and a L-CDR region having nomore than one, two, three, four, five, or six amino acid additions,deletions or substitutions of any of SEQ ID NOs:185-265 (e.g., theantigen binding protein has two CDR regions, one H-CDR and one L-CDH. Aspecific embodiment includes antigen binding proteins comprising both aH-CDR3 and a L-CDR3 region.

As will be appreciated by those in the art, for any antigen bindingprotein comprising more than one CDR from the sequences provided herein,any combination of CDRs independently selected from the CDR in TABLE 1sequences is useful. Thus, antigen binding proteins comprising one, two,three, four, five, or six independently selected CDRs can be generated.However, as will be appreciated by those in the art, specificembodiments generally utilize combinations of CDRs that arenon-repetitive, e.g., antigen binding proteins are generally not madewith two H-CDR2 regions, etc.

In some embodiments, antigen binding proteins are generated thatcomprise no more than one, two, three, four, five, or six amino acidadditions, deletions or substitutions of a H-CDR3 region and a L-CDR3region, particularly with the H-CDR3 region being selected from asequence having no more than one, two, three, four, five, or six aminoacid additions, deletions or substitutions of a H-CDR3 region of any ofSEQ ID NOs:107-184 and the L-CDR3 region being selected from a L-CDR3consensus sequence having no more than one, two, three, four, five, orsix amino acid additions, deletions or substitutions of a L-CDR3 regionof any of SEQ ID SEQ ID NOs:185-265.

As noted herein, the antigen binding proteins of the present inventioncomprise a scaffold structure into which the CDR(s) of the invention maybe grafted. The genus of IL-17RA antigen binding proteins comprises thesubgenus of antibodies, as variously defined herein. Aspects includeembodiments wherein the scaffold structure is a traditional, tetramericantibody structure. Thus, the antigen binding protein combinationsdescribed herein include the additional components (framework, J and Dregions, constant regions, etc.) that make up a heavy and/or lightchain.

Embodiments include the use of human scaffold components. An exemplaryembodiment of a VH variable region grafted into a traditional antibodyscaffold structure is depicted in SEQ ID NO:427 and an exemplaryembodiment of a VL variable region grafted into a traditional antibodyscaffold structure is depicted in SEQ ID NO:429. Of course it isunderstood that any antibody scaffold known in the art may be employed.

In one aspect, the present invention provides antibodies that comprise alight chain variable region selected from the group consisting ofAM_(L)1 through AM_(L)26 and/or a heavy chain variable region selectedfrom the group consisting of AM_(H)1 through AM_(H)26, and fragments,derivatives, muteins, and variants thereof. Antibodies of the inventioninclude, but are not limited to: antibodies comprising AM_(L)1/AM_(H)1(SEQ ID NO:27/SEQ ID NO:1), AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2),AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3), AM_(L)4/AM_(H)4 (SEQ IDNO:30/SEQ ID NO:4), AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5),AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6), AM_(L)7/AM_(H)7 (SEQ IDNO:33/SEQ ID NO:7), AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8),AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9), AM_(L)10/AM_(H)10 (SEQ IDNO:36/SEQ ID NO:10), AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11),AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12), AM_(L)13/AM_(H)13 (SEQ IDNO:39/SEQ ID NO:13), AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14),AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15), AM_(L)16/AM_(H)16 (SEQ IDNO:42/SEQ ID NO:16), AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17),AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18), AM_(L)19/AM_(H)19 (SEQ IDNO:45/SEQ ID NO:19), AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20),AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21), AM_(L)22/AM_(H)22 (SEQ IDNO:48/SEQ ID NO:22), AM_(L)23/AM_(H)23 (SEQ ID NO:49 or SEQ ID NO:50/SEQID NO:23), AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24),AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25), AM_(L)26/AM_(H)26 (SEQ IDNO:53/SEQ ID NO:26), as well as IL-17RA-binding fragments thereof andcombinations thereof.

In one embodiment, the present invention provides an antibody comprisinga light chain variable domain comprising a sequence of amino acids thatdiffers from the sequence of a light chain variable domain selected fromthe group consisting of AM_(L)1 through AM_(L)26 only at 15, 14, 13, 12,11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residues, wherein each suchsequence difference is independently either a deletion, insertion, orsubstitution of one amino acid residue. In another embodiment, thelight-chain variable domain comprises a sequence of amino acids that isat least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to thesequence of a light chain variable domain selected from the groupconsisting of AM_(L)1 through AM_(L)26. In another embodiment, the lightchain variable domain comprises a sequence of amino acids that isencoded by a nucleotide sequence that is at least 70%, 75%, 80%, 85%,90%, 95%, 97%, or 99% identical to a nucleotide sequence that encodes alight chain variable domain selected from the group consisting ofAM_(L)1 through AM_(L)26. In another embodiment, the light chainvariable domain comprises a sequence of amino acids that is encoded by apolynucleotide that hybridizes under moderately stringent conditions tothe complement of a polynucleotide that encodes a light chain variabledomain selected from the group consisting of AM_(L)1 through AM_(L)26.In another embodiment, the light chain variable domain comprises asequence of amino acids that is encoded by a polynucleotide thathybridizes under moderately stringent conditions to the complement of apolynucleotide that encodes a light chain variable domain selected fromthe group consisting of AM_(L)1 through AM_(L)26. In another embodiment,the light chain variable domain comprises a sequence of amino acids thatis encoded by a polynucleotide that hybridizes under moderatelystringent conditions to a complement of a light chain polynucleotideprovided in any one of AM_(L)1 through AM_(L)26 polynucleotide sequences(SEQ ID NOs:80-106).

In another embodiment, the present invention provides an antibodycomprising a heavy chain variable domain comprising a sequence of aminoacids that differs from the sequence of a heavy chain variable domainselected from the group consisting of AM_(H)1 through AM_(H)26 only at15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 residue(s), whereineach such sequence difference is independently either a deletion,insertion, or substitution of one amino acid residue. In anotherembodiment, the heavy chain variable domain comprises a sequence ofamino acids that is at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the sequence of a heavy chain variable domain selected fromthe group consisting of AM_(H)1 through AM_(H)26. In another embodiment,the heavy chain variable domain comprises a sequence of amino acids thatis encoded by a nucleotide sequence that is at least 70%, 75%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% identical to a nucleotide sequence that encodes aheavy chain variable domain selected from the group consisting ofAM_(H)1 through AM_(H)26. In another embodiment, the heavy chainvariable domain comprises a sequence of amino acids that is encoded by apolynucleotide that hybridizes under moderately stringent or stringentconditions to the complement of a polynucleotide that encodes a heavychain variable domain selected from the group consisting of AM_(H)1through AM_(H)26. In another embodiment, the heavy chain variable domaincomprises a sequence of amino acids that is encoded by a polynucleotidethat hybridizes under moderately stringent conditions to the complementof a polynucleotide that encodes a heavy chain variable domain selectedfrom the group consisting of AM_(H)1 through AM_(H)26. In anotherembodiment, the heavy chain variable domain comprises a sequence ofamino acids that is encoded by a polynucleotide that hybridizes undermoderately stringent or stringent conditions to a complement of a heavychain polynucleotide provided in any one of AM_(H)1 through AM_(H)26polynucleotide sequences (SEQ ID NOs:54-79).

Accordingly, in various embodiments, the antigen binding proteins of theinvention comprise the scaffolds of traditional antibodies, includinghuman and monoclonal antibodies, bispecific antibodies, diabodies,minibodies, domain antibodies, synthetic antibodies (sometimes referredto herein as “antibody mimetics”), chimeric antibodies, antibody fusions(sometimes referred to as “antibody conjugates”), and fragments of each,respectively. The above described CDRs and combinations of CDRs may begrafted into any of the following scaffolds.

As used herein, the term “antibody” refers to the various forms ofmonomeric or multimeric proteins comprising one or more polypeptidechains that specifically binds to an antigen, as variously describedherein. In certain embodiments, antibodies are produced by recombinantDNA techniques. In additional embodiments, antibodies are produced byenzymatic or chemical cleavage of naturally occurring antibodies. Inanother aspect, the antibody is selected from the group consisting of:a) a human antibody; b) a humanized antibody; c) a chimeric antibody; d)a monoclonal antibody; e) a polyclonal antibody; f) a recombinantantibody; g) an antigen-binding antibody fragment; h) a single chainantibody; i) a diabody; j) a triabody; k) a tetrabody; l) a Fabfragment; m) a F(ab′)₂ fragment; n) an IgD antibody; o) an IgE antibody;p) an IgM antibody; q) an IgA antibody; r) an IgG1 antibody; s) an IgG2antibody; t) an IgG3 antibody; and u) an IgG4 antibody.

A variable region comprises at least three heavy or light chain CDRs,see, supra (Kabat et al., 1991, Sequences of Proteins of ImmunologicalInterest, Public Health Service N.I.H., Bethesda, Md.; see also Chothiaand Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature342: 877-883), embedded within a framework region (designated frameworkregions 1-4, FR1, FR2, FR3, and FR4, by Kabat et al., 1991, supra; seealso Chothia and Lesk, 1987, supra). See, infra.

Traditional antibody structural units typically comprise a tetramer.Each tetramer is typically composed of two identical pairs ofpolypeptide chains, each pair having one “light” (typically having amolecular weight of about 25 kDa) and one “heavy” chain (typicallyhaving a molecular weight of about 50-70 kDa). The amino-terminalportion of each chain includes a variable region of about 100 to 110 ormore amino acids primarily responsible for antigen recognition. Thecarboxy-terminal portion of each chain defines a constant regionprimarily responsible for effector function. Human light chains areclassified as kappa and lambda light chains. Heavy chains are classifiedas mu, delta, gamma, alpha, or epsilon, and define the antibody'sisotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has severalsubclasses, including, but not limited to IgG1, IgG2, IgG3, and IgG4.IgM has subclasses, including, but not limited to, IgM1 and IgM2.Embodiments of the invention include all such classes of antibodies thatincorporate the variable domains or the CDRs of the antigen bindingproteins, as described herein.

Within light and heavy chains, the variable and constant regions arejoined by a “J” region of about twelve (12) or more amino acids, withthe heavy chain also including a “D” region of about ten (10) more aminoacids. See, generally, Paul, W., ed., 1989, Fundamental Immunology Ch.7, 2nd ed. Raven Press, N.Y. The variable regions of each light/heavychain pair form the antibody binding site. Scaffolds of the inventioninclude such regions.

Some naturally occurring antibodies, for example found in camels andllamas, are dimers consisting of two heavy chain and include no lightchains. Muldermans et al., 2001, J. Biotechnol. 74:277-302; Desmyter etal., 2001, J. Biol. Chem. 276:26285-26290. Crystallographic studies of acamel antibody have revealed that the CDR3 regions form a surface thatinteracts with the antigen and thus is critical for antigen binding likein the more typical tetrameric antibodies. The invention encompassesdimeric antibodies consisting of two heavy chains, or fragments thereof,that can bind to and/or inhibit the biological activity of IL-17RA.

The variable regions of the heavy and light chains typically exhibit thesame general structure of relatively conserved framework regions (FR)joined by three hypervariable regions, i.e., the complementaritydetermining regions or CDRs. The CDRs are the hypervariable regions ofan antibody (or antigen binding protein, as outlined herein), that areresponsible for antigen recognition and binding. The CDRs from the twochains of each pair are aligned by the framework regions, enablingbinding to a specific epitope. From N-terminal to C-terminal, both lightand heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3and FR4. The assignment of amino acids to each domain is in accordancewith the definitions of Kabat Sequences of Proteins of ImmunologicalInterest. Chothia et al., 1987, J. Mol. Biol. 196:901-917; Chothia etal., 1989, Nature 342:878-883. Scaffolds of the invention include suchregions.

CDRs constitute the major surface contact points for antigen binding.See, e.g., Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917. Further,CDR3 of the light chain and, especially, CDR3 of the heavy chain mayconstitute the most important determinants in antigen binding within thelight and heavy chain variable regions. See, e.g., Chothia and Lesk,1987, supra; Desiderio et al., 2001, J. Mol. Biol. 310:603-615; Xu andDavis, 2000, Immunity 13:37-45; Desmyter et al., 2001, J. Biol. Chem.276:26285-26290; and Muyldermans, 2001, J. Biotechnol. 74:277-302. Insome antibodies, the heavy chain CDR3 appears to constitute the majorarea of contact between the antigen and the antibody. Desmyter et al.,2001, supra. In vitro selection schemes in which CDR3 alone is variedcan be used to vary the binding properties of an antibody. Muyldermans,2001, supra; Desiderio et al., 2001, supra.

Naturally occurring antibodies typically include a signal sequence,which directs the antibody into the cellular pathway for proteinsecretion and which is not present in the mature antibody. Apolynucleotide encoding an antibody of the invention may encode anaturally occurring signal sequence or a heterologous signal sequence asdescribed below.

In one embodiment, the antigen binding protein is a monoclonal antibody,comprising from one (1) to six (6) of the depicted CDRs, as outlinedherein (see TABLE 1). The antibodies of the invention may be of any typeincluding IgM, IgG (including IgG1, IgG2, IgG3, IgG4), IgD, IgA, or IgEantibody. In specific embodiment, the antigen binding protein is an IgGtype antibody. In an even more specific embodiment, the antigen bindingprotein is an IgG2 type antibody.

In some embodiments, for example when the antigen binding protein is anantibody with complete heavy and light chains, the CDRs are all from thesame species, e.g., human. Alternatively, for example in embodimentswherein the antigen binding protein contains less than six CDRs from thesequences outlined above, additional CDRs may be either from otherspecies (e.g., murine CDRs), or may be different human CDRs than thosedepicted in the sequences. For example, human H-CDR3 and L-CDR3 regionsfrom the appropriate sequences identified herein may be used, withH-CDR1, H-CDR2, L-CDR1 and L-CDR2 being optionally selected fromalternate species, or different human antibody sequences, orcombinations thereof. For example, the CDRs of the invention can replacethe CDR regions of commercially relevant chimeric or humanizedantibodies.

Specific embodiments utilize scaffold components of the antigen bindingproteins that are human components.

In some embodiments, however, the scaffold components can be a mixturefrom different species. As such, if the antigen binding protein is anantibody, such antibody may be a chimeric antibody and/or a humanizedantibody. In general, both “chimeric antibodies” and “humanizedantibodies” refer to antibodies that combine regions from more than onespecies. For example, “chimeric antibodies” traditionally comprisevariable region(s) from a mouse (or rat, in some cases) and the constantregion(s) from a human.

“Humanized antibodies” generally refer to non-human antibodies that havehad the variable-domain framework regions swapped for sequences found inhuman antibodies. Generally, in a humanized antibody, the entireantibody, except the CDRs, is encoded by a polynucleotide of humanorigin or is identical to such an antibody except within its CDRs. TheCDRs, some or all of which are encoded by nucleic acids originating in anon-human organism, are grafted into the beta-sheet framework of a humanantibody variable region to create an antibody, the specificity of whichis determined by the engrafted CDRs. The creation of such antibodies isdescribed in, e.g., WO 92/11018, Jones, 1986, Nature 321:522-525,Verhoeyen et al., 1988, Science 239:1534-1536. Humanized antibodies canalso be generated using mice with a genetically engineered immunesystem. Roque et al., 2004, Biotechnol. Prog. 20:639-654. In the presentinvention, the identified CDRs are human, and thus both humanized andchimeric antibodies in this context include some non-human CDRs; forexample, humanized antibodies may be generated that comprise the CDRH3and CDRL3 regions, with one or more of the other CDR regions being of adifferent special origin.

In one embodiment, the IL-17RA antigen binding protein is amultispecific antibody, and notably a bispecific antibody, alsosometimes referred to as “diabodies”. These are antibodies that bind totwo (or more) different antigens. Diabodies can be manufactured in avariety of ways known in the art (Holliger and Winter, 1993, CurrentOpinion Biotechnol. 4:446-449), e.g., prepared chemically or from hybridhybridomas.

In one embodiment, the IL-17RA antigen binding protein is a minibody.Minibodies are minimized antibody-like proteins comprising a scFv joinedto a CH3 domain. Hu et al., 1996, Cancer Res. 56:3055-3061. In oneembodiment, the IL-17RA antigen binding protein is a domain antibody;see, for example U.S. Pat. No. 6,248,516. Domain antibodies (dAbs) arefunctional binding domains of antibodies, corresponding to the variableregions of either the heavy (VH) or light (VL) chains of humanantibodies dABs have a molecular weight of approximately 13 kDa, or lessthan one-tenth the size of a full antibody. dABs are well expressed in avariety of hosts including bacterial, yeast, and mammalian cell systems.In addition, dAbs are highly stable and retain activity even after beingsubjected to harsh conditions, such as freeze-drying or heatdenaturation. See, for example, U.S. Pat. Nos. 6,291,158; 6,582,915;6,593,081; 6,172,197; US Serial No. 2004/0110941; European Patent0368684; U.S. Pat. No. 6,696,245, WO04/058821, WO04/003019 andWO03/002609.

In one embodiment, the IL-17RA antigen binding protein is an antibodyfragment, that is a fragment of any of the antibodies outlined hereinthat retain binding specificity to IL-17RA. In various embodiments, theantibody binding proteins comprise, but are not limited to, a F(ab),F(ab′), F(ab′)2, Fv, or a single chain Fv fragments. At a minimum, anantibody, as meant herein, comprises a polypeptide that can bindspecifically to IL-17RA comprising all or part of a light or heavy chainvariable region, such as one or more CDRs.

Further examples of IL-17RA-binding antibody fragments include, but arenot limited to, (i) the Fab fragment consisting of VL, VH, CL and CH1domains, (ii) the Fd fragment consisting of the VH and CH1 domains,(iii) the Fv fragment consisting of the VL and VH domains of a singleantibody; (iv) the dAb fragment (Ward et al., 1989, Nature 341:544-546)which consists of a single variable, (v) isolated CDR regions, (vi)F(ab′)₂ fragments, a bivalent fragment comprising two linked Fabfragments (vii) single chain Fv molecules (scFv), wherein a VH domainand a VL domain are linked by a peptide linker which allows the twodomains to associate to form an antigen binding site (Bird et al., 1988,Science 242:423-426, Huston et al., 1988, Proc. Natl. Acad. Sci. USA.85:5879-5883), (viii) bispecific single chain Fv dimers (PCT/US92/09965)and (ix) “diabodies” or “triabodies”, multivalent or multispecificfragments constructed by gene fusion (Tomlinson et. al., 2000, MethodsEnzymol. 326:461-479; WO94/13804; Holliger et al., 1993, Proc. Natl.Acad. Sci. U.S.A. 90:6444-6448). The antibody fragments may be modified.For example, the molecules may be stabilized by the incorporation ofdisulphide bridges linking the VH and VL domains (Reiter et al., 1996,Nature Biotech. 14:1239-1245). Aspects of the invention includeembodiments wherein the non-CDR components of these fragments are humansequences.

In one embodiment, the IL-17RA antigen binding protein is a fully humanantibody. In this embodiment, as outlined above, specific structurescomprise complete heavy and light chains depicted comprising the CDRregions. Additional embodiments utilize one or more of the CDRs of theinvention, with the other CDRs, framework regions, J and D regions,constant regions, etc., coming from other human antibodies. For example,the CDRs of the invention can replace the CDRs of any number of humanantibodies, particularly commercially relevant antibodies

Single chain antibodies may be formed by linking heavy and light chainvariable domain (Fv region) fragments via an amino acid bridge (shortpeptide linker), resulting in a single polypeptide chain. Suchsingle-chain Fvs (scFvs) have been prepared by fusing DNA encoding apeptide linker between DNAs encoding the two variable domainpolypeptides (V_(L) and V_(H)). The resulting polypeptides can fold backon themselves to form antigen-binding monomers, or they can formmultimers (e.g., dimers, trimers, or tetramers), depending on the lengthof a flexible linker between the two variable domains (Kortt et al.,1997, Prot. Eng. 10:423; Kortt et al., 2001, Biomol. Eng. 18:95-108). Bycombining different V_(L) and V_(H)-comprising polypeptides, one canform multimeric scFvs that bind to different epitopes (Kriangkum et al.,2001, Biomol. Eng. 18:31-40). Techniques developed for the production ofsingle chain antibodies include those described in U.S. Pat. No.4,946,778; Bird, 1988, Science 242:423; Huston et al., 1988, Proc. Natl.Acad. Sci. USA 85:5879; Ward et al., 1989, Nature 334:544, de Graaf etal., 2002, Methods Mol. Biol. 178:379-87. Single chain antibodiesderived from antibodies provided herein (including but not limited toscFvs comprising the variable domain combinations of AM_(L)1/AM_(H)1(SEQ ID NO:27/SEQ ID NO:1), AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2),AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3), AM_(L)4/AM_(H)4 (SEQ IDNO:30/SEQ ID NO:4), AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5),AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6), AM_(L)7/AM_(H)7 (SEQ IDNO:33/SEQ ID NO:7), AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8),AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9), AM_(L)10/AM_(H)10 (SEQ IDNO:36/SEQ ID NO:10), AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11),AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12), AM_(L)13/AM_(H)13 (SEQ IDNO:39/SEQ ID NO:13), AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14),AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15), AM_(L)16/AM_(H)16 (SEQ IDNO:42/SEQ ID NO:16), AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17),AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18), AM_(L)19/AM_(H)19 (SEQ IDNO:45/SEQ ID NO:19), AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20),AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21), AM_(L)22/AM_(H)22 (SEQ IDNO:48/SEQ ID NO:22), AM_(L)23/AM_(H)23 (SEQ ID NO:49 or SEQ ID NO:50/SEQID NO:23), AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24),AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25), AM_(L)26/AM_(H)26 (SEQ IDNO:53/SEQ ID NO:26), and combinations thereof are encompassed by thepresent invention.

In one embodiment, the IL-17RA antigen binding protein is an antibodyfusion protein (sometimes referred to herein as an “antibodyconjugate”). The conjugate partner can be proteinaceous ornon-proteinaceous; the latter generally being generated using functionalgroups on the antigen binding protein (see the discussion on covalentmodifications of the antigen binding proteins) and on the conjugatepartner. For example linkers are known in the art; for example, homo- orhetero-bifunctional linkers as are well known (see, 1994 Pierce ChemicalCompany catalog, technical section on cross-linkers, pages 155-200,incorporated herein by reference).

In one embodiment, the IL-17RA antigen binding protein is an antibodyanalog, sometimes referred to as “synthetic antibodies.” For example, avariety of recent work utilizes either alternative protein scaffolds orartificial scaffolds with grafted CDRs. Such scaffolds include, but arenot limited to, mutations introduced to stabilize the three-dimensionalstructure of the binding protein as well as wholly synthetic scaffoldsconsisting for example of biocompatible polymers. See, for example,Korndorfer et al., 2003, Proteins: Structure, Function, andBioinformatics, Volume 53, Issue 1:121-129. Roque et al., 2004,Biotechnol. Prog. 20:639-654. In addition, peptide antibody mimetics(“PAMs”) can be used, as well as work based on antibody mimeticsutilizing fibronection components as a scaffold.

As it is known in the art, a number of different programs can be used toidentify the degree of sequence identity or similarity a protein ornucleic acid has to a known sequence.

By “protein,” as used herein, is meant at least two covalently attachedamino acids, which includes proteins, polypeptides, oligopeptides andpeptides. In some embodiments, the two or more covalently attached aminoacids are attached by a peptide bond. The protein may be made up ofnaturally occurring amino acids and peptide bonds, for example when theprotein is made recombinantly using expression systems and host cells,as outlined below. Alternatively, the protein may include syntheticamino acids (e.g., homophenylalanine, citrulline, ornithine, andnorleucine), or peptidomimetic structures, i.e., “peptide or proteinanalogs”, such as peptoids (see, Simon et al., 1992, Proc. Natl. Acad.Sci. U.S.A. 89:9367, incorporated by reference herein), which can beresistant to proteases or other physiological and/or storage conditions.Such synthetic amino acids may be incorporated in particular when theantigen binding protein is synthesized in vitro by conventional methodswell known in the art. In addition, any combination of peptidomimetic,synthetic and naturally occurring residues/structures can be used.“Amino acid” also includes imino acid residues such as proline andhydroxyproline. The amino acid “R group” or “side chain” may be ineither the (L)- or the (S)-configuration. In a specific embodiment, theamino acids are in the (L)- or (S)-configuration.

In certain aspects, the invention provides recombinant antigen bindingproteins that bind an IL-17RA, in some embodiments a recombinant humanIL-17RA or portion thereof. In this context, a “recombinant protein” isa protein made using recombinant techniques using any techniques andmethods known in the art, i.e., through the expression of a recombinantnucleic acid as described herein. Methods and techniques for theproduction of recombinant proteins are well known in the art.Embodiments of the invention include recombinant antigen bindingproteins that bind wild-type IL-17RA and variants thereof.

“Consisting essentially of” means that the amino acid sequence can varyby about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% relativeto the recited SEQ ID NO: sequence and still retain biological activity,as described herein.

In some embodiments, the antigen binding proteins of the invention areisolated proteins or substantially pure proteins. An “isolated” proteinis unaccompanied by at least some of the material with which it isnormally associated in its natural state, for example constituting atleast about 5%, or at least about 50% by weight of the total protein ina given sample. It is understood that the isolated protein mayconstitute from 5 to 99.9% by weight of the total protein contentdepending on the circumstances. For example, the protein may be made ata significantly higher concentration through the use of an induciblepromoter or high expression promoter, such that the protein is made atincreased concentration levels. The definition includes the productionof an antigen binding protein in a wide variety of organisms and/or hostcells that are known in the art.

For amino acid sequences, sequence identity and/or similarity isdetermined by using standard techniques known in the art, including, butnot limited to, the local sequence identity algorithm of Smith andWaterman, 1981, Adv. Appl. Math. 2:482, the sequence identity alignmentalgorithm of Needleman and Wunsch, 1970, J. Mol. Biol. 48:443, thesearch for similarity method of Pearson and Lipman, 1988, Proc. Nat.Acad. Sci. U.S.A. 85:2444, computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Drive, Madison,Wis.), the Best Fit sequence program described by Devereux et al., 1984,Nucl. Acid Res. 12:387-395, preferably using the default settings, or byinspection. Preferably, percent identity is calculated by FastDB basedupon the following parameters: mismatch penalty of 1; gap penalty of 1;gap size penalty of 0.33; and joining penalty of 30, “Current Methods inSequence Comparison and Analysis,” Macromolecule Sequencing andSynthesis, Selected Methods and Applications, pp 127-149 (1988), Alan R.Liss, Inc.

An example of a useful algorithm is PILEUP. PILEUP creates a multiplesequence alignment from a group of related sequences using progressive,pairwise alignments. It can also plot a tree showing the clusteringrelationships used to create the alignment. PILEUP uses a simplificationof the progressive alignment method of Feng & Doolittle, 1987, J. Mol.Evol. 35:351-360; the method is similar to that described by Higgins andSharp, 1989, CABIOS 5:151-153. Useful PILEUP parameters including adefault gap weight of 3.00, a default gap length weight of 0.10, andweighted end gaps.

Another example of a useful algorithm is the BLAST algorithm, describedin: Altschul et al., 1990, J. Mol. Biol. 215:403-410; Altschul et al.,1997, Nucleic Acids Res. 25:3389-3402; and Karin et al., 1993, Proc.Natl. Acad. Sci. U.S.A. 90:5873-5787. A particularly useful BLASTprogram is the WU-BLAST-2 program which was obtained from Altschul etal., 1996, Methods in Enzymology 266:460-480. WU-BLAST-2 uses severalsearch parameters, most of which are set to the default values. Theadjustable parameters are set with the following values: overlap span=1,overlap fraction=0.125, word threshold (T)=II. The HSP S and HSP S2parameters are dynamic values and are established by the program itselfdepending upon the composition of the particular sequence andcomposition of the particular database against which the sequence ofinterest is being searched; however, the values may be adjusted toincrease sensitivity.

An additional useful algorithm is gapped BLAST as reported by Altschulet al., 1993, Nucl. Acids Res. 25:3389-3402. Gapped BLAST uses BLOSUM-62substitution scores; threshold T parameter set to 9; the two-hit methodto trigger ungapped extensions, charges gap lengths of k a cost of 10+k;X_(u) set to 16, and X_(g) set to 40 for database search stage and to 67for the output stage of the algorithms. Gapped alignments are triggeredby a score corresponding to about 22 bits.

Generally, the amino acid homology, similarity, or identity betweenindividual variant CDRs are at least 80% to the sequences depictedherein, and more typically with preferably increasing homologies oridentities of at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, and almost 100%. In a similar manner, “percent (%) nucleic acidsequence identity” with respect to the nucleic acid sequence of thebinding proteins identified herein is defined as the percentage ofnucleotide residues in a candidate sequence that are identical with thenucleotide residues in the coding sequence of the antigen bindingprotein. A specific method utilizes the BLASTN module of WU-BLAST-2 setto the default parameters, with overlap span and overlap fraction set to1 and 0.125, respectively.

Generally, the nucleic acid sequence homology, similarity, or identitybetween the nucleotide sequences encoding individual variant CDRs andthe nucleotide sequences depicted herein are at least 80%, and moretypically with preferably increasing homologies or identities of atleast 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99%, and almost 100%.

Thus, a “variant CDR” is one with the specified homology, similarity, oridentity to the parent CDR of the invention, and shares biologicalfunction, including, but not limited to, at least 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% of the specificity and/or activity of the parent CDR.

While the site or region for introducing an amino acid sequencevariation is predetermined, the mutation per se need not bepredetermined. For example, in order to optimize the performance of amutation at a given site, random mutagenesis may be conducted at thetarget codon or region and the expressed antigen binding protein CDRvariants screened for the optimal combination of desired activity.Techniques for making substitution mutations at predetermined sites inDNA having a known sequence are well known, for example, M13 primermutagenesis and PCR mutagenesis. Screening of the mutants is done usingassays of antigen binding protein activities, such as IL-17RA binding.

Amino acid substitutions are typically of single residues; insertionsusually will be on the order of from about one (1) to about twenty (20)amino acid residues, although considerably larger insertions may betolerated. Deletions range from about one (1) to about twenty (20) aminoacid residues, although in some cases deletions may be much larger.

Substitutions, deletions, insertions or any combination thereof may beused to arrive at a final derivative or variant. Generally these changesare done on a few amino acids to minimize the alteration of themolecule, particularly the immunogenicity and specificity of the antigenbinding protein. However, larger changes may be tolerated in certaincircumstances. Conservative substitutions are generally made inaccordance with the following chart depicted as TABLE 2.

TABLE 2 Original Exemplary Residue Substitutions Ala Ser Arg Lys AsnGln, His Asp Glu Cys Ser Gln Asn Glu Asp Gly Pro His Asn, Gln Ile Leu,Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe Met, Leu, Tyr SerThr Thr Ser Trp Tyr Tyr Trp, Phe Val Ile, Leu

Substantial changes in function or immunological identity are made byselecting substitutions that are less conservative than those shown inTABLE 2. For example, substitutions may be made which more significantlyaffect: the structure of the polypeptide backbone in the area of thealteration, for example the alpha-helical or beta-sheet structure; thecharge or hydrophobicity of the molecule at the target site; or the bulkof the side chain. The substitutions which in general are expected toproduce the greatest changes in the polypeptide's properties are thosein which (a) a hydrophilic residue, e.g., seryl or threonyl, issubstituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl,phenylalanyl, valyl or alanyl; (b) a cysteine or proline is substitutedfor (or by) any other residue; (c) a residue having an electropositiveside chain, e.g., lysyl, arginyl, or histidyl, is substituted for (orby) an electronegative residue, e.g., glutamyl or aspartyl; or (d) aresidue having a bulky side chain, e.g., phenylalanine, is substitutedfor (or by) one not having a side chain, e.g., glycine.

The variants typically exhibit the same qualitative biological activityand will elicit the same immune response as the naturally-occurringanalogue, although variants also are selected to modify thecharacteristics of the antigen binding protein proteins as needed.Alternatively, the variant may be designed such that the biologicalactivity of the antigen binding protein is altered. For example,glycosylation sites may be altered or removed as discussed herein. Sucha modification of the IL-17RA antigen binding proteins, includingantibodies, is an example of a derivative. A “derivative” of apolypeptide is a polypeptide (e.g., an antibody) that has beenchemically modified, e.g., via conjugation to another chemical moietysuch as, for example, polyethylene glycol, albumin (e.g., human serumalbumin), phosphorylation, and glycosylation.

Other derivatives of IL-17RA antibodies within the scope of thisinvention include covalent or aggregative conjugates of IL-17RAantibodies, or fragments thereof, with other proteins or polypeptides,such as by expression of recombinant fusion proteins comprisingheterologous polypeptides fused to the N-terminus or C-terminus of anIL-17RA antibody polypeptide. For example, the conjugated peptide may bea heterologous signal (or leader) polypeptide, e.g., the yeastalpha-factor leader, or a peptide such as an epitope tag. IL-17RAantibody-containing fusion proteins can comprise peptides added tofacilitate purification or identification of the IL-17RA antibody (e.g.,poly-His). An IL-17RA antibody polypeptide also can be linked to theFLAG peptide DYKDDDDK (SEQ ID NO:447) as described in Hopp et al.,Bio/Technology 6:1204, 1988, and U.S. Pat. No. 5,011,912. The FLAGpeptide is highly antigenic and provides an epitope reversibly bound bya specific monoclonal antibody (mAb), enabling rapid assay and facilepurification of expressed recombinant protein. Reagents useful forpreparing fusion proteins in which the FLAG peptide is fused to a givenpolypeptide are commercially available (Sigma, St. Louis, Mo.).

Oligomers that contain one or more IL-17RA antibody polypeptides may beemployed as IL-17RA antagonists. Oligomers may be in the form ofcovalently-linked or non-covalently-linked dimers, trimers, or higheroligomers. Oligomers comprising two or more IL-17RA antibodypolypeptides are contemplated for use, with one example being ahomodimer. Other oligomers include heterodimers, homotrimers,heterotrimers, homotetramers, heterotetramers, etc.

One embodiment is directed to oligomers comprising multiple IL-17RAantibody polypeptides joined via covalent or non-covalent interactionsbetween peptide moieties fused to the IL-17RA antibody polypeptides.Such peptides may be peptide linkers (spacers), or peptides that havethe property of promoting oligomerization. Leucine zippers and certainpolypeptides derived from antibodies are among the peptides that canpromote oligomerization of IL-17RA antibody polypeptides attachedthereto, as described in more detail below.

In particular embodiments, the oligomers comprise from two to fourIL-17RA antibody polypeptides. The IL-17RA antibody moieties of theoligomer may be in any of the forms described above, e.g., variants orfragments. Preferably, the oligomers comprise IL-17RA antibodypolypeptides that have IL-17RA binding activity.

In one embodiment, an oligomer is prepared using polypeptides derivedfrom immunoglobulins. Preparation of Fusion Proteins Comprising CertainHeterologous Polypeptides Fused to Various Portions of antibody-derivedpolypeptides (including the Fc domain) has been described, e.g., byAshkenazi et al., 1991, PNAS USA 88:10535; Byrn et al., 1990, Nature344:677; and Hollenbaugh et al., 1992 “Construction of ImmunoglobulinFusion Proteins”, in Current Protocols in Immunology, Suppl. 4, pages10.19.1-10.19.11.

One embodiment of the present invention is directed to a dimercomprising two fusion proteins created by fusing an IL-17RA bindingfragment of an IL-17RA antibody to the Fc region of an antibody. Thedimer can be made by, for example, inserting a gene fusion encoding thefusion protein into an appropriate expression vector, expressing thegene fusion in host cells transformed with the recombinant expressionvector, and allowing the expressed fusion protein to assemble much likeantibody molecules, whereupon interchain disulfide bonds form betweenthe Fc moieties to yield the dimer.

The term “Fc polypeptide” as used herein includes native and muteinforms of polypeptides derived from the Fc region of an antibody.Truncated forms of such polypeptides containing the hinge region thatpromotes dimerization also are included. Fusion proteins comprising Fcmoieties (and oligomers formed therefrom) offer the advantage of facilepurification by affinity chromatography over Protein A or Protein Gcolumns.

One suitable Fc polypeptide, described in PCT application WO 93/10151(hereby incorporated by reference), is a single chain polypeptideextending from the N-terminal hinge region to the native C-terminus ofthe Fc region of a human IgG antibody. Another useful Fc polypeptide isthe Fc mutein described in U.S. Pat. No. 5,457,035 and in Baum et al.,1994, EMBO J. 13:3992-4001. The amino acid sequence of this mutein isidentical to that of the native Fc sequence presented in WO 93/10151,except that amino acid 19 has been changed from Leu to Ala, amino acid20 has been changed from Leu to Glu, and amino acid 22 has been changedfrom Gly to Ala. The mutein exhibits reduced affinity for Fc receptors.

In other embodiments, the variable portion of the heavy and/or lightchains of an IL-17RA antibody may be substituted for the variableportion of an antibody heavy and/or light chain.

Alternatively, the oligomer is a fusion protein comprising multipleIL-17RA antibody polypeptides, with or without peptide linkers (spacerpeptides). Among the suitable peptide linkers are those described inU.S. Pat. Nos. 4,751,180 and 4,935,233.

Another method for preparing oligomeric IL-17RA antibody derivativesinvolves use of a leucine zipper. Leucine zipper domains are peptidesthat promote oligomerization of the proteins in which they are found.Leucine zippers were originally identified in several DNA-bindingproteins (Landschulz et al., 1988, Science 240:1759), and have sincebeen found in a variety of different proteins. Among the known leucinezippers are naturally occurring peptides and derivatives thereof thatdimerize or trimerize. Examples of leucine zipper domains suitable forproducing soluble oligomeric proteins are described in PCT applicationWO 94/10308, and the leucine zipper derived from lung surfactant proteinD (SPD) described in Hoppe et al., 1994, FEBS Letters 344:191, herebyincorporated by reference. The use of a modified leucine zipper thatallows for stable trimerization of a heterologous protein fused theretois described in Fanslow et al., 1994, Semin. Immunol. 6:267-78. In oneapproach, recombinant fusion proteins comprising an IL-17RA antibodyfragment or derivative fused to a leucine zipper peptide are expressedin suitable host cells, and the soluble oligomeric IL-17RA antibodyfragments or derivatives that form are recovered from the culturesupernatant.

Covalent modifications are also considered derivatives of the IL-17RAantigen binding proteins and are included within the scope of thisinvention, and are generally, but not always, done post-translationally.For example, several types of covalent modifications of the antigenbinding protein are introduced into the molecule by reacting specificamino acid residues of the antigen binding protein with an organicderivatizing agent that is capable of reacting with selected side chainsor the N- or C-terminal residues.

Cysteinyl residues most commonly are reacted with α-haloacetates (andcorresponding amines), such as chloroacetic acid or chloroacetamide, togive carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residuesalso are derivatized by reaction with bromotrifluoroacetone,α-bromo-β-(5-imidozoyl)propionic acid, chloroacetyl phosphate,N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyldisulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, orchloro-7-nitrobenzo-2-oxa-1,3-diazole.

Histidyl residues are derivatized by reaction with diethylpyrocarbonateat pH 5.5-7.0 because this agent is relatively specific for the histidylside chain. Para-bromophenacyl bromide also is useful; the reaction ispreferably performed in 0.1M sodium cacodylate at pH 6.0.

Lysinyl and amino terminal residues are reacted with succinic or othercarboxylic acid anhydrides. Derivatization with these agents has theeffect of reversing the charge of the lysinyl residues. Other suitablereagents for derivatizing alpha-amino-containing residues includeimidoesters such as methyl picolinimidate; pyridoxal phosphate;pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid;O-methylisourea; 2,4-pentanedione; and transaminase-catalyzed reactionwith glyoxylate.

Arginyl residues are modified by reaction with one or severalconventional reagents, among them phenylglyoxal, 2,3-butanedione,1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residuesrequires that the reaction be performed in alkaline conditions becauseof the high pK_(a) of the guanidine functional group. Furthermore, thesereagents may react with the groups of lysine as well as the arginineepsilon-amino group.

The specific modification of tyrosyl residues may be made, withparticular interest in introducing spectral labels into tyrosyl residuesby reaction with aromatic diazonium compounds or tetranitromethane. Mostcommonly, N-acetylimidizole and tetranitromethane are used to formO-acetyl tyrosyl species and 3-nitro derivatives, respectively. Tyrosylresidues are iodinated using ¹²⁵I or ¹³¹I to prepare labeled proteinsfor use in radioimmunoassay, the chloramine T method described abovebeing suitable.

Carboxyl side groups (aspartyl or glutamyl) are selectively modified byreaction with carbodiimides (R′—N═C═N—R′), where R and R′ are optionallydifferent alkyl groups, such as 1-cyclohexyl-3-(2-morpholinyl-4-ethyl)carbodiimide or 1-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide.Furthermore, aspartyl and glutamyl residues are converted to asparaginyland glutaminyl residues by reaction with ammonium ions.

Derivatization with bifunctional agents is useful for crosslinkingantigen binding proteins to a water-insoluble support matrix or surfacefor use in a variety of methods. Commonly used crosslinking agentsinclude, e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylicacid, homobifunctional imidoesters, including disuccinimidyl esters suchas 3,3′-dithiobis(succinimidylpropionate), and bifunctional maleimidessuch as bis-N-maleimido-1,8-octane. Derivatizing agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate yield photoactivatableintermediates that are capable of forming crosslinks in the presence oflight. Alternatively, reactive water-insoluble matrices such as cyanogenbromide-activated carbohydrates and the reactive substrates described inU.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537;and 4,330,440 are employed for protein immobilization.

Glutaminyl and asparaginyl residues are frequently deamidated to thecorresponding glutamyl and aspartyl residues, respectively.Alternatively, these residues are deamidated under mildly acidicconditions. Either form of these residues falls within the scope of thisinvention.

Other modifications include hydroxylation of proline and lysine,phosphorylation of hydroxyl groups of seryl or threonyl residues,methylation of the α-amino groups of lysine, arginine, and histidineside chains (T. E. Creighton, Proteins: Structure and MolecularProperties, W. H. Freeman & Co., San Francisco, 1983, pp. 79-86),acetylation of the N-terminal amine, and amidation of any C-terminalcarboxyl group.

Another type of covalent modification of the antigen binding proteinincluded within the scope of this invention comprises altering theglycosylation pattern of the protein. As is known in the art,glycosylation patterns can depend on both the sequence of the protein(e.g., the presence or absence of particular glycosylation amino acidresidues, discussed below), or the host cell or organism in which theprotein is produced. Particular expression systems are discussed below.

Glycosylation of polypeptides is typically either N-linked or O-linked.N-linked refers to the attachment of the carbohydrate moiety to the sidechain of an asparagine residue. The tri-peptide sequencesasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline, are the recognition sequences for enzymaticattachment of the carbohydrate moiety to the asparagine side chain.Thus, the presence of either of these tri-peptide sequences in apolypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid,most commonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

Addition of glycosylation sites to the antigen binding protein isconveniently accomplished by altering the amino acid sequence such thatit contains one or more of the above-described tri-peptide sequences(for N-linked glycosylation sites). The alteration may also be made bythe addition of, or substitution by, one or more serine or threonineresidues to the starting sequence (for O-linked glycosylation sites).For ease, the antigen binding protein amino acid sequence is preferablyaltered through changes at the DNA level, particularly by mutating theDNA encoding the target polypeptide at preselected bases such thatcodons are generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on theantigen binding protein is by chemical or enzymatic coupling ofglycosides to the protein. These procedures are advantageous in thatthey do not require production of the protein in a host cell that hasglycosylation capabilities for N- and O-linked glycosylation. Dependingon the coupling mode used, the sugar(s) may be attached to (a) arginineand histidine, (b) free carboxyl groups, (c) free sulfhydryl groups suchas those of cysteine, (d) free hydroxyl groups such as those of serine,threonine, or hydroxyproline, (e) aromatic residues such as those ofphenylalanine, tyrosine, or tryptophan, or (f) the amide group ofglutamine. These methods are described in WO 87/05330 published Sep. 11,1987, and in Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp.259-306.

Removal of carbohydrate moieties present on the starting antigen bindingprotein may be accomplished chemically or enzymatically. Chemicaldeglycosylation requires exposure of the protein to the compoundtrifluoromethanesulfonic acid, or an equivalent compound. This treatmentresults in the cleavage of most or all sugars except the linking sugar(N-acetylglucosamine or N-acetylgalactosamine), while leaving thepolypeptide intact. Chemical deglycosylation is described by Hakimuddinet al., 1987, Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981,Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties onpolypeptides can be achieved by the use of a variety of endo- andexo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol.138:350. Glycosylation at potential glycosylation sites may be preventedby the use of the compound tunicamycin as described by Duskin et al.,1982, J. Biol. Chem. 257:3105. Tunicamycin blocks the formation ofprotein-N-glycoside linkages.

Another type of covalent modification of the antigen binding proteincomprises linking the antigen binding protein to variousnonproteinaceous polymers, including, but not limited to, variouspolyols such as polyethylene glycol, polypropylene glycol orpolyoxyalkylenes, in the manner set forth in U.S. Pat. No. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337. In addition, asis known in the art, amino acid substitutions may be made in variouspositions within the antigen binding protein to facilitate the additionof polymers such as PEG.

In some embodiments, the covalent modification of the antigen bindingproteins of the invention comprises the addition of one or more labels.

The term “labelling group” means any detectable label. Examples ofsuitable labelling groups include, but are not limited to, thefollowing: radioisotopes or radionuclides (e.g., ³H, ¹⁴C, ¹⁵N, ³⁵S, ⁹⁰Y,⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I), fluorescent groups (e.g., FITC, rhodamine,lanthanide phosphors), enzymatic groups (e.g., horseradish peroxidase,β-galactosidase, luciferase, alkaline phosphatase), chemiluminescentgroups, biotinyl groups, or predetermined polypeptide epitopesrecognized by a secondary reporter (e.g., leucine zipper pair sequences,binding sites for secondary antibodies, metal binding domains, epitopetags). In some embodiments, the labelling group is coupled to theantigen binding protein via spacer arms of various lengths to reducepotential steric hindrance. Various methods for labelling proteins areknown in the art and may be used in performing the present invention.

In general, labels fall into a variety of classes, depending on theassay in which they are to be detected: a) isotopic labels, which may beradioactive or heavy isotopes; b) magnetic labels (e.g., magneticparticles); c) redox active moieties; d) optical dyes; enzymatic groups(e.g. horseradish peroxidase, β-galactosidase, luciferase, alkalinephosphatase); e) biotinylated groups; and f) predetermined polypeptideepitopes recognized by a secondary reporter (e.g., leucine zipper pairsequences, binding sites for secondary antibodies, metal bindingdomains, epitope tags, etc.). In some embodiments, the labelling groupis coupled to the antigen binding protein via spacer arms of variouslengths to reduce potential steric hindrance. Various methods forlabelling proteins are known in the art and may be used in performingthe present invention.

Specific labels include optical dyes, including, but not limited to,chromophores, phosphors and fluorophores, with the latter being specificin many instances. Fluorophores can be either “small molecule” fluores,or proteinaceous fluores.

By “fluorescent label” is meant any molecule that may be detected viaits inherent fluorescent properties. Suitable fluorescent labelsinclude, but are not limited to, fluorescein, rhodamine,tetramethylrhodamine, eosin, erythrosin, coumarin, methyl-coumarins,pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade BlueJ, TexasRed, IAEDANS, EDANS, BODIPY FL, LC Red 640, Cy 5, Cy 5.5, LC Red 705,Oregon green, the Alexa-Fluor dyes (Alexa Fluor 350, Alexa Fluor 430,Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594,Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680), Cascade Blue,Cascade Yellow and R-phycoerythrin (PE) (Molecular Probes, Eugene,Oreg.), FITC, Rhodamine, and Texas Red (Pierce, Rockford, Ill.), Cy5,Cy5.5, Cy7 (Amersham Life Science, Pittsburgh, Pa.). Suitable opticaldyes, including fluorophores, are described in Molecular Probes Handbookby Richard P. Haugland, hereby expressly incorporated by reference.

Suitable proteinaceous fluorescent labels also include, but are notlimited to, green fluorescent protein, including a Renilla, Ptilosarcus,or Aequorea species of GFP (Chalfie et al., 1994, Science 263:802-805),EGFP (Clontech Laboratories, Inc., Genbank Accession Number U55762),blue fluorescent protein (BFP, Quantum Biotechnologies, Inc. 1801 deMaisonneuve Blvd. West, 8th Floor, Montreal, Quebec, Canada H3H 1J9;Stauber, 1998, Biotechniques 24:462-471; Heim et al., 1996, Curr. Biol.6:178-182), enhanced yellow fluorescent protein (EYFP, ClontechLaboratories, Inc.), luciferase (Ichiki et al., 1993, J. Immunol.150:5408-5417), β galactosidase (Nolan et al., 1988, Proc. Natl. Acad.Sci. USA. 85:2603-2607) and Renilla (WO92/15673, WO95/07463, WO98/14605,WO98/26277, WO99/49019, U.S. Pat. Nos. 5,292,658, 5,418,155, 5,683,888,5,741,668, 5,777,079, 5,804,387, 5,874,304, 5,876,995, 5,925,558). Allof the above-cited references are expressly incorporated herein byreference.

Polynucleotides Encoding IL-17RA Antigen Binding Proteins

Encompassed within the invention are nucleic acids encoding IL-17RAantigen binding proteins, including antibodies, as defined herein. Thepolynucleotide sequences for the heavy chain variable regions AM_(H)1-26are found in SEQ ID NOs:54-79, respectively, and the polynucleotidesequences for the light chain variable regions AM_(L)1-26 are found inSEQ ID NOs:80-106, respectively, with AM_(L)23 having two version, asshown in SEQ ID NO:102 and 103. The SEQ ID NOs for the polynucleotidesequences encoding the H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2, andL-CDR3 are provided in TABLE 1.

Aspects of the invention include polynucleotide variants (e.g., due todegeneracy) that encode the amino acid sequences described herein.

Aspects of the invention include a variety of embodiments including, butnot limited to, the following exemplary embodiments: embodiment 51: anisolated polynucleotide, wherein said polynucleotide encodes apolypeptide comprising an amino acid sequence selected from the groupconsisting of:

A.

-   -   a. a light chain variable domain sequence that is at least 80%        identical to a light chain variable domain sequence of        AM_(L)1-26 (SEQ ID NOs:27-53, respectively);    -   b. a heavy chain variable domain sequence that is at least 80%        identical to a heavy chain variable domain sequence of        AM_(H)1-26 (SEQ ID NOs:1-26, respectively); or    -   c. the light chain variable domain of (a) and the heavy chain        variable domain of (b); and

B. a light chain CDR1, CDR2, CDR3 and a heavy chain CDR1, CDR2, CDR3that differs by no more than a total of three amino acid additions,substitutions, and/or deletions in each CDR from the followingsequences:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26;    -   wherein said polypeptide specifically binds IL-17 receptor A.

Embodiment 52: the polynucleotide of embodiment 51, wherein saidpolynucleotide hybridizes under stringent conditions to the full lengthcomplement of a polynucleotide selected from the group consisting of:

-   -   a. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)1/AM_(H)1 (SEQ ID NO:80/SEQ ID NO:54);    -   b. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)2/AM_(H)2 (SEQ ID NO:81/SEQ ID NO:55);    -   c. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)3/AM_(H)3 (SEQ ID NO:82/SEQ ID NO:56);    -   d. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)4/AM_(H)4 (SEQ ID NO:83/SEQ ID NO:57);    -   e. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)5/AM_(H)5 (SEQ ID NO:84/SEQ ID NO:58);    -   f. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)6/AM_(H)6 (SEQ ID NO:85/SEQ ID NO:59)    -   g. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)7/AM_(H)7 (SEQ ID NO:86/SEQ ID NO:60);    -   h. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)8/AM_(H)8 (SEQ ID NO:87/SEQ ID NO:61);    -   i. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)9/AM_(H)9 (SEQ ID NO:88/SEQ ID NO:62);    -   j. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)10/AM_(H)10 (SEQ ID NO:89/SEQ ID NO:63);    -   k. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)11/AM_(H)11 (SEQ ID NO:90/SEQ ID NO:64);    -   l. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)12/AM_(H)12 (SEQ ID NO:91/SEQ ID NO:65);    -   m. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)13/AM_(H)13 (SEQ ID NO:92/SEQ ID NO:66);    -   n. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)14/AM_(H)14 (SEQ ID NO:93/SEQ ID NO:67);    -   o. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)15/AM_(H)15 (SEQ ID NO:94/SEQ ID NO:68);    -   p. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)16/AM_(H)16 (SEQ ID NO:95/SEQ ID NO:69);    -   q. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)17/AM_(H)17 (SEQ ID NO:96/SEQ ID NO:70);    -   r. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)18/AM_(H)18 (SEQ ID NO:97/SEQ ID NO:71);    -   s. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)19/AM_(H)19 (SEQ ID NO:98/SEQ ID NO:72);    -   t. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)20/AM_(H)20 (SEQ ID NO:99/SEQ ID NO:73);    -   u. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)21/AM_(H)21 (SEQ ID NO:100/SEQ ID NO:74);    -   v. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)22/AM_(H)22 (SEQ ID NO:10/SEQ ID NO:75);    -   w. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)23/AM_(H)23 (SEQ ID NO:102 or SEQ ID NO:103/SEQ ID NO:76);    -   x. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)24/AM_(H)24 (SEQ ID NO:104/SEQ ID NO:77);    -   y. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)25/AM_(H)25 (SEQ ID NO:105/SEQ ID NO:78); and    -   z. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)26/AM_(H)26 (SEQ ID NO:106/SEQ ID NO:79).

Embodiment 53: the polynucleotide of embodiment 51, wherein saidpolynucleotide hybridizes under stringent conditions to the full lengthcomplement of a polynucleotide selected from the group consisting of:

-   -   a. a light chain CDR1-encoding polynucleotide of SEQ ID NO:345,        CDR2-encoding polynucleotide of SEQ ID NO:346, CDR3-encoding        polynucleotide of SEQ ID NO:347 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:266, CDR2-encoding polynucleotide of        SEQ ID NO:267, and CDR3-encoding polynucleotide of SEQ ID NO:268        of antibody AM-1;    -   b. a light chain CDR1-encoding polynucleotide of SEQ ID NO:348,        CDR2-encoding polynucleotide of SEQ ID NO:349, CDR3-encoding        polynucleotide of SEQ ID NO:350 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:269, CDR2-encoding polynucleotide of        SEQ ID NO:270, CDR3-encoding polynucleotide of SEQ ID NO:271 of        antibody AM-2;    -   c. a light chain CDR1-encoding polynucleotide of SEQ ID NO:351,        CDR2-encoding polynucleotide of SEQ ID NO:352, CDR3-encoding        polynucleotide of SEQ ID NO:353 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:272, CDR2-encoding polynucleotide of        SEQ ID NO:273, CDR3-encoding polynucleotide of SEQ ID NO:274 of        antibody AM-3;    -   d. a light chain CDR1-encoding polynucleotide of SEQ ID NO:354,        CDR2-encoding polynucleotide of SEQ ID NO:355, CDR3-encoding        polynucleotide of SEQ ID NO:356 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:275, CDR2-encoding polynucleotide of        SEQ ID NO:276, CDR3-encoding polynucleotide of SEQ ID NO:277 of        antibody AM-4;    -   e. a light chain CDR1-encoding polynucleotide of SEQ ID NO:357,        CDR2-encoding polynucleotide of SEQ ID NO:358, CDR3-encoding        polynucleotide of SEQ ID NO:359 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:278, CDR2-encoding polynucleotide of        SEQ ID NO:279, CDR3-encoding polynucleotide of SEQ ID NO:280 of        antibody AM-5;    -   f. a light chain CDR1-encoding polynucleotide of SEQ ID NO:360,        CDR2-encoding polynucleotide of SEQ ID NO:361, CDR3-encoding        polynucleotide of SEQ ID NO:362 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:281, CDR2-encoding polynucleotide of        SEQ ID NO:282, CDR3-encoding polynucleotide of SEQ ID NO:283 of        antibody AM-6;    -   g. a light chain CDR1-encoding polynucleotide of SEQ ID NO:363,        CDR2-encoding polynucleotide of SEQ ID NO:364, CDR3-encoding        polynucleotide of SEQ ID NO:365 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:284, CDR2-encoding polynucleotide of        SEQ ID NO:285, CDR3-encoding polynucleotide of SEQ ID NO:286 of        antibody AM-7;    -   h. a light chain CDR1-encoding polynucleotide of SEQ ID NO:366,        CDR2-encoding polynucleotide of SEQ ID NO:367, CDR3-encoding        polynucleotide of SEQ ID NO:368 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:287, CDR2-encoding polynucleotide of        SEQ ID NO:288, CDR3-encoding polynucleotide of SEQ ID NO:289 of        antibody AM-8;    -   i. a light chain CDR1-encoding polynucleotide of SEQ ID NO:369,        CDR2-encoding polynucleotide of SEQ ID NO:370, CDR3-encoding        polynucleotide of SEQ ID NO:371 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:290, CDR2-encoding polynucleotide of        SEQ ID NO:291, CDR3-encoding polynucleotide of SEQ ID NO:292 of        antibody AM-9;    -   j. a light chain CDR1-encoding polynucleotide of SEQ ID NO:372,        CDR2-encoding polynucleotide of SEQ ID NO:373, CDR3-encoding        polynucleotide of SEQ ID NO:374 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:293, CDR2-encoding polynucleotide of        SEQ ID NO:294, CDR3-encoding polynucleotide of SEQ ID NO:295 of        antibody AM-10;    -   k. a light chain CDR1-encoding polynucleotide of SEQ ID NO:375,        CDR2-encoding polynucleotide of SEQ ID NO:376, CDR3-encoding        polynucleotide of SEQ ID NO:377 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:296, CDR2-encoding polynucleotide of        SEQ ID NO:297, CDR3-encoding polynucleotide of SEQ ID NO:298 of        antibody AM-11;    -   l. a light chain CDR1-encoding polynucleotide of SEQ ID NO:378,        CDR2-encoding polynucleotide of SEQ ID NO:379, CDR3-encoding        polynucleotide of SEQ ID NO:380 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:299, CDR2-encoding polynucleotide of        SEQ ID NO:300, CDR3-encoding polynucleotide of SEQ ID NO:301 of        antibody AM-12;    -   m. a light chain CDR1-encoding polynucleotide of SEQ ID NO:381,        CDR2-encoding polynucleotide of SEQ ID NO:382, CDR3-encoding        polynucleotide of SEQ ID NO:383 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:302, CDR2-encoding polynucleotide of        SEQ ID NO:303, CDR3-encoding polynucleotide of SEQ ID NO:304 of        antibody AM-13;    -   n. a light chain CDR1-encoding polynucleotide of SEQ ID NO:384,        CDR2-encoding polynucleotide of SEQ ID NO:385, CDR3-encoding        polynucleotide of SEQ ID NO:386 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:305, CDR2-encoding polynucleotide of        SEQ ID NO:306, CDR3-encoding polynucleotide of SEQ ID NO:307 of        antibody AM-14;    -   o. a light chain CDR1-encoding polynucleotide of SEQ ID NO:387,        CDR2-encoding polynucleotide of SEQ ID NO:388, CDR3-encoding        polynucleotide of SEQ ID NO:389 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:308, CDR2-encoding polynucleotide of        SEQ ID NO:309, CDR3-encoding polynucleotide of SEQ ID NO:310 of        antibody AM-15;    -   p. a light chain CDR1-encoding polynucleotide of SEQ ID NO:390,        CDR2-encoding polynucleotide of SEQ ID NO:391, CDR3-encoding        polynucleotide of SEQ ID NO:392 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:311, CDR2-encoding polynucleotide of        SEQ ID NO:312, CDR3-encoding polynucleotide of SEQ ID NO:313 of        antibody AM-16;    -   q. a light chain CDR1-encoding polynucleotide of SEQ ID NO:393,        CDR2-encoding polynucleotide of SEQ ID NO:394, CDR3-encoding        polynucleotide of SEQ ID NO:395 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:314, CDR2-encoding polynucleotide of        SEQ ID NO:315, CDR3-encoding polynucleotide of SEQ ID NO:316 of        antibody AM-17;    -   r. a light chain CDR1-encoding polynucleotide of SEQ ID NO:396,        CDR2-encoding polynucleotide of SEQ ID NO:397, CDR3-encoding        polynucleotide of SEQ ID NO:398 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:317, CDR2-encoding polynucleotide of        SEQ ID NO:318, CDR3-encoding polynucleotide of SEQ ID NO:319 of        antibody AM-18;    -   s. a light chain CDR1-encoding polynucleotide of SEQ ID NO:399,        CDR2-encoding polynucleotide of SEQ ID NO:400, CDR3-encoding        polynucleotide of SEQ ID NO:401 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:320, CDR2-encoding polynucleotide of        SEQ ID NO:321, CDR3-encoding polynucleotide of SEQ ID NO:322 of        antibody AM-19;    -   t. a light chain CDR1-encoding polynucleotide of SEQ ID NO:402,        CDR2-encoding polynucleotide of SEQ ID NO:403, CDR3-encoding        polynucleotide of SEQ ID NO:404 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:323, CDR2-encoding polynucleotide of        SEQ ID NO:324, CDR3-encoding polynucleotide of SEQ ID NO:325 of        antibody AM-20;    -   u. a light chain CDR1-encoding polynucleotide of SEQ ID NO:405,        CDR2-encoding polynucleotide of SEQ ID NO:406, CDR3-encoding        polynucleotide of SEQ ID NO:407 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:326, CDR2-encoding polynucleotide of        SEQ ID NO:327, CDR3-encoding polynucleotide of SEQ ID NO:328 of        antibody AM-21;    -   v. a light chain CDR1-encoding polynucleotide of SEQ ID NO:408,        CDR2-encoding polynucleotide of SEQ ID NO:409, CDR3-encoding        polynucleotide of SEQ ID NO:410 and a heavy chain CDR1 SEQ ID        NO:329, CDR2-encoding polynucleotide of SEQ ID NO:330,        CDR3-encoding polynucleotide of SEQ ID NO:331 of antibody AM-22;    -   w. a light chain CDR1-encoding polynucleotide of SEQ ID NO:411,        CDR2-encoding polynucleotide of SEQ ID NO:412, CDR3-encoding        polynucleotide of SEQ ID NO:413 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:332, CDR2-encoding polynucleotide of        SEQ ID NO:333, CDR3-encoding polynucleotide of SEQ ID NO:334 of        antibody AM-23;    -   x. a light chain CDR1-encoding polynucleotide of SEQ ID NO:414,        CDR2-encoding polynucleotide of SEQ ID NO:415, CDR3-encoding        polynucleotide of SEQ ID NO:416 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:332, CDR2-encoding polynucleotide of        SEQ ID NO:333, CDR3-encoding polynucleotide of SEQ ID NO:334 of        antibody AM-23;    -   y. a light chain CDR1-encoding polynucleotide of SEQ ID NO:417,        CDR2-encoding polynucleotide of SEQ ID NO:418, CDR3-encoding        polynucleotide of SEQ ID NO:419 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:335, CDR2-encoding polynucleotide of        SEQ ID NO:336, CDR3-encoding polynucleotide of SEQ ID NO:337 of        antibody AM-24;    -   z. a light chain CDR1-encoding polynucleotide of SEQ ID NO:420,        CDR2-encoding polynucleotide of SEQ ID NO:421, CDR3-encoding        polynucleotide of SEQ ID NO:422 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:338, CDR2-encoding polynucleotide of        SEQ ID NO:339, CDR3-encoding polynucleotide of SEQ ID NO:340 of        antibody AM-25; or    -   z.2. a light chain CDR1-encoding polynucleotide of SEQ ID        NO:423, CDR2-encoding polynucleotide of SEQ ID NO:424,        CDR3-encoding polynucleotide of SEQ ID NO:425 and a heavy chain        CDR1-encoding polynucleotide of SEQ ID NO:341, CDR2-encoding        polynucleotide of SEQ ID NO:342, CDR3-encoding polynucleotide of        SEQ ID NO:343 of antibody AM-26.

Embodiment 54: the polynucleotide of embodiment 51, wherein saidpolynucleotide encodes a polypeptide comprising an amino acid sequenceselected from the group consisting of:

-   -   a. a light chain variable domain and a heavy chain variable        domain of AM_(L)1/AM_(H)1 (SEQ ID NO:27/SEQ ID NO:1);    -   b. a light chain variable domain and a heavy chain variable        domain of AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2);    -   c. a light chain variable domain and a heavy chain variable        domain of AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3);    -   d. a light chain variable domain and a heavy chain variable        domain of AM_(L)4/AM_(H)4 (SEQ ID NO:30/SEQ ID NO:4);    -   e. a light chain variable domain and a heavy chain variable        domain of AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5);    -   f. a light chain variable domain and a heavy chain variable        domain of AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6)    -   g. a light chain variable domain and a heavy chain variable        domain of AM_(L)7/AM_(H)7 (SEQ ID NO:33/SEQ ID NO:7);    -   h. a light chain variable domain and a heavy chain variable        domain of AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8);    -   i. a light chain variable domain and a heavy chain variable        domain of AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9);    -   j. a light chain variable domain and a heavy chain variable        domain of AM_(L)10/AM_(H)10 (SEQ ID NO:36/SEQ ID NO:10);    -   k. a light chain variable domain and a heavy chain variable        domain of AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11);    -   l. a light chain variable domain and a heavy chain variable        domain of AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12);    -   m. a light chain variable domain and a heavy chain variable        domain of AM_(L)13/AM_(H)13 (SEQ ID NO:39/SEQ ID NO:13);    -   n. a light chain variable domain and a heavy chain variable        domain of AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14);    -   o. a light chain variable domain and a heavy chain variable        domain of AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15);    -   p. a light chain variable domain and a heavy chain variable        domain of AM_(L)16/AM_(H)16 (SEQ ID NO:42/SEQ ID NO:16);    -   q. a light chain variable domain and a heavy chain variable        domain of AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17);    -   r. a light chain variable domain and a heavy chain variable        domain of AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18);    -   s. a light chain variable domain and a heavy chain variable        domain of AM_(L)19/AM_(H)19 (SEQ ID NO:45/SEQ ID NO:19);    -   t. a light chain variable domain and a heavy chain variable        domain of AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20);    -   u. a light chain variable domain and a heavy chain variable        domain of AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21);    -   v. a light chain variable domain and a heavy chain variable        domain of AM_(L)22/AM_(H)22 (SEQ ID NO:48/SEQ ID NO:22);    -   w. a light chain variable domain and a heavy chain variable        domain of AM_(L)23/AM_(H)23 (SEQ ID NO: 49 or SEQ ID NO:50/SEQ        ID NO:23);    -   x. a light chain variable domain and a heavy chain variable        domain of AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24);    -   y. a light chain variable domain and a heavy chain variable        domain of AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25); and    -   z. a light chain variable domain and a heavy chain variable        domain of AM_(L)26/AM_(H)26 (SEQ ID NO:53/SEQ ID NO:26).

Embodiment 55. The polynucleotide of embodiment 51, wherein saidpolynucleotide encodes a polypeptide comprising an amino acid sequenceselected from the group consisting of:

-   -   a. a light chain CDR1 (SEQ ID NO:185), CDR2 (SEQ ID NO:186),        CDR3 (SEQ ID NO:187) and a heavy chain CDR1 (SEQ ID NO:107),        CDR2 (SEQ ID NO:108), CDR3 (SEQ ID NO:109) of antibody AM-1;    -   b. a light chain CDR1 (SEQ ID NO:188), CDR2 (SEQ ID NO:189),        CDR3 (SEQ ID NO:190) and a heavy chain CDR1 (SEQ ID NO:110),        CDR2 (SEQ ID NO:111), CDR3 (SEQ ID NO:112) of antibody AM-2;    -   c. a light chain CDR1 (SEQ ID NO:191), CDR2 (SEQ ID NO:192),        CDR3 (SEQ ID NO:193) and a heavy chain CDR1 (SEQ ID NO:113),        CDR2 (SEQ ID NO:114), CDR3 (SEQ ID NO:115) of antibody AM-3;    -   d. a light chain CDR1 (SEQ ID NO:194), CDR2 (SEQ ID NO:195),        CDR3 (SEQ ID NO:196) and a heavy chain CDR1 (SEQ ID NO:116),        CDR2 (SEQ ID NO:117), CDR3 (SEQ ID NO:118) of antibody AM-4;    -   e. a light chain CDR1 (SEQ ID NO:197), CDR2 (SEQ ID NO:198),        CDR3 (SEQ ID NO:199) and a heavy chain CDR1 (SEQ ID NO:119),        CDR2 (SEQ ID NO:120), CDR3 (SEQ ID NO:121) of antibody AM-5;    -   f. a light chain CDR1 (SEQ ID NO:200), CDR2 (SEQ ID NO:201),        CDR3 (SEQ ID NO:202) and a heavy chain CDR1 (SEQ ID NO:122),        CDR2 (SEQ ID NO:123), CDR3 (SEQ ID NO:124) of antibody AM-6;    -   g. a light chain CDR1 (SEQ ID NO:203), CDR2 (SEQ ID NO:204),        CDR3 (SEQ ID NO:205) and a heavy chain CDR1 (SEQ ID NO:125),        CDR2 (SEQ ID NO:126), CDR3 (SEQ ID NO:127) of antibody AM-7;    -   h. a light chain CDR1 (SEQ ID NO:206), CDR2 (SEQ ID NO:207),        CDR3 (SEQ ID NO:208) and a heavy chain CDR1 (SEQ ID NO:128),        CDR2 (SEQ ID NO:129), CDR3 (SEQ ID NO:130) of antibody AM-8;    -   i. a light chain CDR1 (SEQ ID NO:209), CDR2 (SEQ ID NO:210),        CDR3 (SEQ ID NO:211) and a heavy chain CDR1 (SEQ ID NO:131),        CDR2 (SEQ ID NO:132), CDR3 (SEQ ID NO:133) of antibody AM-9;    -   j. a light chain CDR1 (SEQ ID NO:212), CDR2 (SEQ ID NO:213),        CDR3 (SEQ ID NO:214) and a heavy chain CDR1 (SEQ ID NO:134),        CDR2 (SEQ ID NO:135), CDR3 (SEQ ID NO:136) of antibody AM-10;    -   k. a light chain CDR1 (SEQ ID NO:215), CDR2 (SEQ ID NO:216),        CDR3 (SEQ ID NO:217) and a heavy chain CDR1 (SEQ ID NO:137),        CDR2 (SEQ ID NO:138), CDR3 (SEQ ID NO:139) of antibody AM-11;    -   l. a light chain CDR1 (SEQ ID NO:218), CDR2 (SEQ ID NO:219),        CDR3 (SEQ ID NO:220) and a heavy chain CDR1 (SEQ ID NO:140),        CDR2 (SEQ ID NO:141), CDR3 (SEQ ID NO:142) of antibody AM-12;    -   m. a light chain CDR1 (SEQ ID NO:221), CDR2 (SEQ ID NO:222),        CDR3 (SEQ ID NO:223) and a heavy chain CDR1 (SEQ ID NO:143),        CDR2 (SEQ ID NO:144), CDR3 (SEQ ID NO:145) of antibody AM-13;    -   n. a light chain CDR1 (SEQ ID NO:224), CDR2 (SEQ ID NO:225),        CDR3 (SEQ ID NO:226) and a heavy chain CDR1 (SEQ ID NO:146),        CDR2 (SEQ ID NO:147), CDR3 (SEQ ID NO:148) of antibody AM-14;    -   o. a light chain CDR1 (SEQ ID NO:227), CDR2 (SEQ ID NO:228),        CDR3 (SEQ ID NO:229) and a heavy chain CDR1 (SEQ ID NO:149),        CDR2 (SEQ ID NO:150), CDR3 (SEQ ID NO:151) of antibody AM-15;    -   p. a light chain CDR1 (SEQ ID NO:230), CDR2 (SEQ ID NO:231),        CDR3 (SEQ ID NO:232) and a heavy chain CDR1 (SEQ ID NO:152),        CDR2 (SEQ ID NO:153), CDR3 (SEQ ID NO:154) of antibody AM-16;    -   q. a light chain CDR1 (SEQ ID NO:233), CDR2 (SEQ ID NO:234),        CDR3 (SEQ ID NO:235) and a heavy chain CDR1 (SEQ ID NO:155),        CDR2 (SEQ ID NO:156), CDR3 (SEQ ID NO:157) of antibody AM-17;    -   r. a light chain CDR1 (SEQ ID NO:236), CDR2 (SEQ ID NO:237),        CDR3 (SEQ ID NO:238) and a heavy chain CDR1 (SEQ ID NO:158),        CDR2 (SEQ ID NO:159), CDR3 (SEQ ID NO:160) of antibody AM-18;    -   s. a light chain CDR1 (SEQ ID NO:239), CDR2 (SEQ ID NO:240),        CDR3 (SEQ ID NO:241) and a heavy chain CDR1 (SEQ ID NO:161),        CDR2 (SEQ ID NO:162), CDR3 (SEQ ID NO:163) of antibody AM-19;    -   t. a light chain CDR1 (SEQ ID NO:242), CDR2 (SEQ ID NO:243),        CDR3 (SEQ ID NO:244) and a heavy chain CDR1 (SEQ ID NO:164),        CDR2 (SEQ ID NO:165), CDR3 (SEQ ID NO:166) of antibody AM-20;    -   u. a light chain CDR1 (SEQ ID NO:245), CDR2 (SEQ ID NO:246),        CDR3 (SEQ ID NO:247) and a heavy chain CDR1 (SEQ ID NO:167),        CDR2 (SEQ ID NO:168), CDR3 (SEQ ID NO:169) of antibody AM-21;    -   v. a light chain CDR1 (SEQ ID NO:248), CDR2 (SEQ ID NO:249),        CDR3 (SEQ ID NO:250) and a heavy chain CDR1 (SEQ ID NO:170),        CDR2 (SEQ ID NO:171), CDR3 (SEQ ID NO:172) of antibody AM-22;    -   w. a light chain CDR1 (SEQ ID NO:251), CDR2 (SEQ ID NO:252),        CDR3 (SEQ ID NO:253) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   x. a light chain CDR1 (SEQ ID NO:254), CDR2 (SEQ ID NO:255),        CDR3 (SEQ ID NO:256) and a heavy chain CDR1 (SEQ ID NO:173),        CDR2 (SEQ ID NO:174), CDR3 (SEQ ID NO:175) of antibody AM-23;    -   y. a light chain CDR1 (SEQ ID NO:257), CDR2 (SEQ ID NO:258),        CDR3 (SEQ ID NO:259) and a heavy chain CDR1 (SEQ ID NO:176),        CDR2 (SEQ ID NO:177), CDR3 (SEQ ID NO:178) of antibody AM-24;    -   z. a light chain CDR1 (SEQ ID NO:260), CDR2 (SEQ ID NO:261),        CDR3 (SEQ ID NO:262) and a heavy chain CDR1 (SEQ ID NO:179),        CDR2 (SEQ ID NO:180), CDR3 (SEQ ID NO:181) of antibody AM-25; or    -   z.2. a light chain CDR1 (SEQ ID NO:263), CDR2 (SEQ ID NO:264),        CDR3 (SEQ ID NO:265) and a heavy chain CDR1 (SEQ ID NO:182),        CDR2 (SEQ ID NO:183), CDR3 (SEQ ID NO:184) of antibody AM-26.

Embodiment 6: the polynucleotide of embodiment 2, wherein saidpolynucleotide is selected from the group consisting of:

-   -   a. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)1/AM_(H)1 (SEQ ID NO:80/SEQ ID NO:54);    -   b. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)2/AM_(H)2 (SEQ ID NO:81/SEQ ID NO:55);    -   c. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)3/AM_(H)3 (SEQ ID NO:82/SEQ ID NO:56);    -   d. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)4/AM_(H)4 (SEQ ID NO:83/SEQ ID NO:57);    -   e. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)5/AM_(H)5 (SEQ ID NO:84/SEQ ID NO:58);    -   f. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)6/AM_(H)6 (SEQ ID NO:85/SEQ ID NO:59)    -   g. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)7/AM_(H)7 (SEQ ID NO:86/SEQ ID NO:60);    -   h. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)8/AM_(H)8 (SEQ ID NO:87/SEQ ID NO:61);    -   i. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)9/AM_(H)9 (SEQ ID NO:88/SEQ ID NO:62);    -   j. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)10/AM_(H)10 (SEQ ID NO:89/SEQ ID NO:63);    -   k. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)11/AM_(H)11 (SEQ ID NO:90/SEQ ID NO:64);    -   l. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)12/AM_(H)12 (SEQ ID NO:91/SEQ ID NO:65);    -   m. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)13/AM_(H)13 (SEQ ID NO:92/SEQ ID NO:66);    -   n. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)14/AM_(H)14 (SEQ ID NO:93/SEQ ID NO:67);    -   o. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)15/AM_(H)15 (SEQ ID NO:94/SEQ ID NO:68);    -   p. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)16/AM_(H)16 (SEQ ID NO:95/SEQ ID NO:69);    -   q. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)17/AM_(H)17 (SEQ ID NO:96/SEQ ID NO:70);    -   r. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)18/AM_(H)18 (SEQ ID NO:97/SEQ ID NO:71);    -   s. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)19/AM_(H)19 (SEQ ID NO:98/SEQ ID NO:72);    -   t. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)20/AM_(H)20 (SEQ ID NO:99/SEQ ID NO:73);    -   u. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)21/AM_(H)21 (SEQ ID NO:100/SEQ ID NO:74);    -   v. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)22/AM_(H)22 (SEQ ID NO:101/SEQ ID NO:75);    -   w. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)23/AM_(H)23 (SEQ ID NO:102 or SEQ ID NO:103/SEQ ID NO:76);    -   x. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)24/AM_(H)24 (SEQ ID NO:104/SEQ ID NO:77);    -   y. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)25/AM_(H)25 (SEQ ID NO:105/SEQ ID NO:78); and    -   z. a light chain variable domain-encoding polynucleotide and a        heavy chain variable domain-encoding polynucleotide of        AM_(L)26/AM_(H)26 (SEQ ID NO:106/SEQ ID NO:79).

Embodiment 57: the polynucleotide of embodiment 53, wherein saidpolynucleotide is selected from the group consisting of:

-   -   a. a light chain CDR1-encoding polynucleotide of SEQ ID NO:345,        CDR2-encoding polynucleotide of SEQ ID NO:346, CDR3-encoding        polynucleotide of SEQ ID NO:347 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:266, CDR2-encoding polynucleotide of        SEQ ID NO:267, and CDR3-encoding polynucleotide of SEQ ID NO:268        of antibody AM-1;    -   b. a light chain CDR1-encoding polynucleotide of SEQ ID NO:348,        CDR2-encoding polynucleotide of SEQ ID NO:349, CDR3-encoding        polynucleotide of SEQ ID NO:350 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:269, CDR2-encoding polynucleotide of        SEQ ID NO:270, CDR3-encoding polynucleotide of SEQ ID NO:271 of        antibody AM-2;    -   c. a light chain CDR1-encoding polynucleotide of SEQ ID NO:351,        CDR2-encoding polynucleotide of SEQ ID NO:352, CDR3-encoding        polynucleotide of SEQ ID NO:353 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:272, CDR2-encoding polynucleotide of        SEQ ID NO:273, CDR3-encoding polynucleotide of SEQ ID NO:274 of        antibody AM-3;    -   d. a light chain CDR1-encoding polynucleotide of SEQ ID NO:354,        CDR2-encoding polynucleotide of SEQ ID NO:355, CDR3-encoding        polynucleotide of SEQ ID NO:356 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:275, CDR2-encoding polynucleotide of        SEQ ID NO:276, CDR3-encoding polynucleotide of SEQ ID NO:277 of        antibody AM-4;    -   e. a light chain CDR1-encoding polynucleotide of SEQ ID NO:357,        CDR2-encoding polynucleotide of SEQ ID NO:358, CDR3-encoding        polynucleotide of SEQ ID NO:359 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:278, CDR2-encoding polynucleotide of        SEQ ID NO:279, CDR3-encoding polynucleotide of SEQ ID NO:280 of        antibody AM-5;    -   f. a light chain CDR1-encoding polynucleotide of SEQ ID NO:360,        CDR2-encoding polynucleotide of SEQ ID NO:361, CDR3-encoding        polynucleotide of SEQ ID NO:362 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:281, CDR2-encoding polynucleotide of        SEQ ID NO:282, CDR3-encoding polynucleotide of SEQ ID NO:283 of        antibody AM-6;    -   g. a light chain CDR1-encoding polynucleotide of SEQ ID NO:363,        CDR2-encoding polynucleotide of SEQ ID NO:364, CDR3-encoding        polynucleotide of SEQ ID NO:365 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:284, CDR2-encoding polynucleotide of        SEQ ID NO:285, CDR3-encoding polynucleotide of SEQ ID NO:286 of        antibody AM-7;    -   h. a light chain CDR1-encoding polynucleotide of SEQ ID NO:366,        CDR2-encoding polynucleotide of SEQ ID NO:367, CDR3-encoding        polynucleotide of SEQ ID NO:368 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:287, CDR2-encoding polynucleotide of        SEQ ID NO:288, CDR3-encoding polynucleotide of SEQ ID NO:289 of        antibody AM-8;    -   i. a light chain CDR1-encoding polynucleotide of SEQ ID NO:369,        CDR2-encoding polynucleotide of SEQ ID NO:370, CDR3-encoding        polynucleotide of SEQ ID NO:371 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:290, CDR2-encoding polynucleotide of        SEQ ID NO:291, CDR3-encoding polynucleotide of SEQ ID NO:292 of        antibody AM-9;    -   j. a light chain CDR1-encoding polynucleotide of SEQ ID NO:372,        CDR2-encoding polynucleotide of SEQ ID NO:373, CDR3-encoding        polynucleotide of SEQ ID NO:374 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:293, CDR2-encoding polynucleotide of        SEQ ID NO:294, CDR3-encoding polynucleotide of SEQ ID NO:295 of        antibody AM-10;    -   k. a light chain CDR1-encoding polynucleotide of SEQ ID NO:375,        CDR2-encoding polynucleotide of SEQ ID NO:376, CDR3-encoding        polynucleotide of SEQ ID NO:377 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:296, CDR2-encoding polynucleotide of        SEQ ID NO:297, CDR3-encoding polynucleotide of SEQ ID NO:298 of        antibody AM-11;    -   l. a light chain CDR1-encoding polynucleotide of SEQ ID NO:378,        CDR2-encoding polynucleotide of SEQ ID NO:379, CDR3-encoding        polynucleotide of SEQ ID NO:380 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:299, CDR2-encoding polynucleotide of        SEQ ID NO:300, CDR3-encoding polynucleotide of SEQ ID NO:301 of        antibody AM-12;    -   m. a light chain CDR1-encoding polynucleotide of SEQ ID NO:381,        CDR2-encoding polynucleotide of SEQ ID NO:382, CDR3-encoding        polynucleotide of SEQ ID NO:383 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:302, CDR2-encoding polynucleotide of        SEQ ID NO:303, CDR3-encoding polynucleotide of SEQ ID NO:304 of        antibody AM-13;    -   n. a light chain CDR1-encoding polynucleotide of SEQ ID NO:384,        CDR2-encoding polynucleotide of SEQ ID NO:385, CDR3-encoding        polynucleotide of SEQ ID NO:386 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:305, CDR2-encoding polynucleotide of        SEQ ID NO:306, CDR3-encoding polynucleotide of SEQ ID NO:307 of        antibody AM-14;    -   o. a light chain CDR1-encoding polynucleotide of SEQ ID NO:387,        CDR2-encoding polynucleotide of SEQ ID NO:388, CDR3-encoding        polynucleotide of SEQ ID NO:389 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:308, CDR2-encoding polynucleotide of        SEQ ID NO:309, CDR3-encoding polynucleotide of SEQ ID NO:310 of        antibody AM-15;    -   p. a light chain CDR1-encoding polynucleotide of SEQ ID NO:390,        CDR2-encoding polynucleotide of SEQ ID NO:391, CDR3-encoding        polynucleotide of SEQ ID NO:392 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:311, CDR2-encoding polynucleotide of        SEQ ID NO:312, CDR3-encoding polynucleotide of SEQ ID NO:313 of        antibody AM-16;    -   q. a light chain CDR1-encoding polynucleotide of SEQ ID NO:393,        CDR2-encoding polynucleotide of SEQ ID NO:394, CDR3-encoding        polynucleotide of SEQ ID NO:395 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:314, CDR2-encoding polynucleotide of        SEQ ID NO:315, CDR3-encoding polynucleotide of SEQ ID NO:316 of        antibody AM-17;    -   r. a light chain CDR1-encoding polynucleotide of SEQ ID NO:396,        CDR2-encoding polynucleotide of SEQ ID NO:397, CDR3-encoding        polynucleotide of SEQ ID NO:398 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:317, CDR2-encoding polynucleotide of        SEQ ID NO:318, CDR3-encoding polynucleotide of SEQ ID NO:319 of        antibody AM-18;    -   s. a light chain CDR1-encoding polynucleotide of SEQ ID NO:399,        CDR2-encoding polynucleotide of SEQ ID NO:400, CDR3-encoding        polynucleotide of SEQ ID NO:401 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:320, CDR2-encoding polynucleotide of        SEQ ID NO:321, CDR3-encoding polynucleotide of SEQ ID NO:322 of        antibody AM-19;    -   t. a light chain CDR1-encoding polynucleotide of SEQ ID NO:402,        CDR2-encoding polynucleotide of SEQ ID NO:403, CDR3-encoding        polynucleotide of SEQ ID NO:404 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:323, CDR2-encoding polynucleotide of        SEQ ID NO:324, CDR3-encoding polynucleotide of SEQ ID NO:325 of        antibody AM-20;    -   u. a light chain CDR1-encoding polynucleotide of SEQ ID NO:405,        CDR2-encoding polynucleotide of SEQ ID NO:406, CDR3-encoding        polynucleotide of SEQ ID NO:407 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:326, CDR2-encoding polynucleotide of        SEQ ID NO:327, CDR3-encoding polynucleotide of SEQ ID NO:328 of        antibody AM-21;    -   v. a light chain CDR1-encoding polynucleotide of SEQ ID NO:408,        CDR2-encoding polynucleotide of SEQ ID NO:409, CDR3-encoding        polynucleotide of SEQ ID NO:410 and a heavy chain CDR1 SEQ ID        NO:329, CDR2-encoding polynucleotide of SEQ ID NO:330,        CDR3-encoding polynucleotide of SEQ ID NO:331 of antibody AM-22;    -   w. a light chain CDR1-encoding polynucleotide of SEQ ID NO:411,        CDR2-encoding polynucleotide of SEQ ID NO:412, CDR3-encoding        polynucleotide of SEQ ID NO:413 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:332, CDR2-encoding polynucleotide of        SEQ ID NO:333, CDR3-encoding polynucleotide of SEQ ID NO:334 of        antibody AM-23;    -   x. a light chain CDR1-encoding polynucleotide of SEQ ID NO:414,        CDR2-encoding polynucleotide of SEQ ID NO:415, CDR3-encoding        polynucleotide of SEQ ID NO:416 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:332, CDR2-encoding polynucleotide of        SEQ ID NO:333, CDR3-encoding polynucleotide of SEQ ID NO:334 of        antibody AM-23;    -   y. a light chain CDR1-encoding polynucleotide of SEQ ID NO:417,        CDR2-encoding polynucleotide of SEQ ID NO:418, CDR3-encoding        polynucleotide of SEQ ID NO:419 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:335, CDR2-encoding polynucleotide of        SEQ ID NO:336, CDR3-encoding polynucleotide of SEQ ID NO:337 of        antibody AM-24;    -   z. a light chain CDR1-encoding polynucleotide of SEQ ID NO:420,        CDR2-encoding polynucleotide of SEQ ID NO:421, CDR3-encoding        polynucleotide of SEQ ID NO:422 and a heavy chain CDR1-encoding        polynucleotide of SEQ ID NO:338, CDR2-encoding polynucleotide of        SEQ ID NO:339, CDR3-encoding polynucleotide of SEQ ID NO:340 of        antibody AM-25; or    -   z.2. a light chain CDR1-encoding polynucleotide of SEQ ID        NO:423, CDR2-encoding polynucleotide of SEQ ID NO:424,        CDR3-encoding polynucleotide of SEQ ID NO:425 and a heavy chain        CDR1-encoding polynucleotide of SEQ ID NO:341, CDR2-encoding        polynucleotide of SEQ ID NO:342, CDR3-encoding polynucleotide of        SEQ ID NO:343 of antibody AM-26.

Embodiment 58: an isolated polynucleotide, wherein said polynucleotideencodes a polypeptide comprising

-   -   a. a heavy chain CDR1 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁YGIS (SEQ ID NO:453), wherein X₁ is selected from the            group consisting of R, S and G;    -   b. a heavy chain CDR2 comprising an amino acid sequence selected        from the group consisting of:        -   i. WISX₁YX₂GNTX₃YAQX₄X₅QG (SEQ ID NO:456), wherein X₁ is            selected from the group consisting of A, X₂ is selected from            the group consisting of N, S and K, X₃ is selected from the            group consisting of N and K, X₄ is selected from the group            consisting of K and N, and X₅ is selected from the group            consisting of L and F;    -   c. a heavy chain CDR3 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁QLX₂X₃DY (SEQ ID NO:459), wherein X₁ is selected from            the group consisting of R and K, X₂ is selected from the            group consisting of Y, V, and A, and X₃ is selected from the            group consisting of F and L;        -   ii. X₁QLX₂FDY (SEQ ID NO:460), wherein X₁ is selected from            the group consisting of R and K, and X₂ is selected from the            group consisting of Y and V;    -   d. a light chain CDR1 comprising an amino acid sequence selected        from the group consisting of:        -   i. RASQSX₁X₂X₃X₄LA (SEQ ID NO:462), wherein X₁ is selected            from the group consisting of V and I, X₂ is selected from            the group consisting of I and S, X₃ is selected from the            group consisting of S and T, X₄ is selected from the group            consisting of N and S, and X₅ is selected from the group            consisting of A and N, and        -   ii. RASQSX₁SSNLA (SEQ ID NO:471), wherein X₁ is selected            from the group consisting of V and I;    -   e. a light chain CDR2 comprising an amino acid sequence selected        from the group consisting of:        -   i. X₁X₂STRAX₃ (SEQ ID NO:466), wherein X₁ is selected from            the group consisting of G and D, X₂ is selected from the            group consisting of A and T, and X₃ is selected from the            group consisting of T and A, and        -   ii. X₁ASTRAX₂ (SEQ ID NO:472), wherein X₁ is selected from            the group consisting of G and D, and X₂ is selected from the            group consisting of A and T; and    -   f. a light chain CDR3 comprising an amino acid sequence selected        from the group consisting of:        -   i. QQYDX₁WPLT (SEQ ID NO:469), wherein X₁ is selected from            the group consisting of N, T, and I;            wherein said polypeptide specifically binds IL-17 receptor            A.

Embodiment 59. The polynucleotide of embodiment 58, wherein saidpolynucleotide encodes a polypeptide wherein said polypeptide comprises:

-   -   a. a heavy chain CDR1 amino acid sequence comprising X₁YGIS (SEQ        ID NO:453), wherein X₁ is selected from the group consisting of        R, S and G;    -   b. a heavy chain CDR2 amino acid sequence comprising        WISX₁YX₂GNTX₃YAQX₄X₅QG (SEQ ID NO:456), wherein X₁ is selected        from the group consisting of A, X₂ is selected from the group        consisting of N, S and K, X₃ is selected from the group        consisting of N and K, X₄ is selected from the group consisting        of K and N, and X₅ is selected from the group consisting of L        and F;    -   c. a heavy chain CDR3 amino acid sequence comprising X₁QLX₂FDY        (SEQ ID NO:460), wherein X₁ is selected from the group        consisting of R and K, and X₂ is selected from the group        consisting of Y and V;    -   d. a light chain CDR1 amino acid sequence comprising        RASQSX₁SSNLA (SEQ ID NO:471), wherein X₁ is selected from the        group consisting of V and I;    -   e. a light chain CDR2 amino acid sequence comprising X₁ASTRAX₂        (SEQ ID NO:472), wherein X₁ is selected from the group        consisting of G and D, and X₂ is selected from the group        consisting of A and T; and    -   f. a light chain CDR3 amino acid sequence comprising QQYDX₁WPLT        (SEQ ID NO:469), wherein X₁ is selected from the group        consisting of N, T, and I; wherein said polypeptide specifically        binds IL-17 receptor A.

Embodiment 60: a plasmid, comprising said polynucleotide of embodiment51. Embodiment 61: the plasmid of embodiment 60, wherein said plasmid isan expression vector. Embodiment 62: an isolated cell, comprising saidplasmid of embodiment 60. Embodiment 63: the isolated cell of embodiment62, wherein a chromosome of said cell comprises said polynucleotide.Embodiment 64: the isolated cell of embodiment 62, wherein said cell isa hybridoma. Embodiment 65: the isolated cell of embodiment 62, whereinsaid cell comprises the expression vector of embodiment 61.

Embodiment 66: the isolated cell of embodiment 65, wherein said cell isa selected from the group consisting of: a. a prokaryotic cell; b. aeukaryotic cell; c. a mammalian cell; d. an insect cell; and e. a CHOcell. Embodiment 67: a method of making a polypeptide that specificallybinds IL-17 receptor A, comprising incubating said isolated cell ofembodiment 65 under conditions that allow it to express saidpolypeptide. Embodiment 68: the polynucleotide of embodiment 51, whereinsaid polynucleotide encodes said polypeptide and wherein saidpolypeptide is an antibody that specifically binds IL-17 receptor A,wherein said antibody is selected from the group consisting of: a. ahumanized antibody; b. a chimeric antibody; c. a recombinant antibody;d. a single chain antibody; e. a diabody; f. a triabody; g. a tetrabody;h. a Fab fragment; i. a F(ab′)2 fragment; j. an IgD antibody; k. an IgEantibody; l. an IgM antibody; m. an IgG1 antibody; n. an IgG2 antibody;o. an IgG3 antibody; and p. an IgG4 antibody.

Embodiment 69: the polynucleotide of embodiment 68, wherein saidpolynucleotide encodes said antibody and wherein said antibody isselected from the group consisting of:

-   -   a) an antibody consisting of a heavy chain sequence of SEQ ID        NO:427 and a light chain sequence of SEQ ID NO:429;    -   b) an antibody consisting essentially of a heavy chain sequence        of SEQ ID NO:427 and a light chain sequence of SEQ ID NO:429;    -   c) an antibody comprising a heavy chain sequence of SEQ ID NO:        427;    -   d) an antibody comprising a light chain sequence of SEQ ID        NO:429;    -   e) an antibody comprising a heavy chain sequence of SEQ ID NO:        427 and a light chain sequence of SEQ ID NO:429;    -   f) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain sequence of SEQ ID NO: 427;    -   g) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain sequence of SEQ ID NO:429;    -   h) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain sequence of SEQ ID NO:427 and a light        chain sequence of SEQ ID NO:429;    -   i) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain variable region sequence of SEQ ID        NO:14;    -   j) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain variable region sequence of SEQ ID        NO:40;    -   k) an antibody or an IL-17 receptor A binding fragment thereof        comprising a light chain variable region sequence of SEQ ID        NO:40 and a heavy chain variable region sequence of SEQ ID        NO:14;    -   l) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain CDR1 of SEQ ID NO:146, a heavy chain        CDR2 of SEQ ID NO:147, a heavy chain CDR3 of SEQ ID NO:148, a        light chain CDR1 of SEQ ID NO:224, a light chain CDR2 of SEQ ID        NO:225, and a light chain CDR3 of SEQ ID NO:226; and    -   m) an antibody or an IL-17 receptor A binding fragment thereof        comprising a heavy chain CDR3 of SEQ ID NO:148 and a light chain        CDR3 of SEQ ID NO:226; wherein said antibody specifically binds        IL-17 receptor A.

Embodiment 70: the polynucleotide of embodiment 69, wherein saidantibody comprises a polynucleotide selected from the group consistingof:

-   -   a) a heavy chain-encoding polynucleotide sequence consisting of        SEQ ID NO:426 and a light chain-encoding polynucleotide sequence        consisting of SEQ ID NO:428;    -   b) a heavy chain-encoding polynucleotide sequence consisting        essentially of SEQ ID NO:426 and a light chain-encoding        polynucleotide sequence consisting essentially of SEQ ID NO:428;    -   c) a heavy chain-encoding polynucleotide sequence comprising SEQ        ID NO: 426;    -   d) a light chain-encoding polynucleotide sequence comprising SEQ        ID NO:428;    -   e) a heavy chain-encoding polynucleotide sequence comprising SEQ        ID NO: 426 and a light chain-encoding polynucleotide sequence        comprising SEQ ID NO:428;    -   f) a heavy chain or an IL-17 receptor A binding fragment        thereof-encoding polynucleotide sequence comprising SEQ ID NO:        426;    -   g) a light chain or an IL-17 receptor A binding fragment        thereof-encoding polynucleotide sequence comprising SEQ ID        NO:428;    -   h) a heavy chain or an IL-17 receptor A binding fragment        thereof-encoding polynucleotide sequence comprising SEQ ID        NO:426 and a light chain or an IL-17 receptor A binding fragment        thereof-encoding polynucleotide sequence comprising SEQ ID        NO:428;    -   i) a heavy chain variable region or an IL-17 receptor A binding        fragment thereof-encoding polynucleotide sequence comprising SEQ        ID NO:67;    -   j) a light chain variable region or an IL-17 receptor A binding        fragment thereof-encoding polynucleotide sequence comprising SEQ        ID NO:93;    -   k) a heavy chain variable region or an IL-17 receptor A binding        fragment thereof-encoding polynucleotide sequence comprising SEQ        ID NO:67 and a light chain variable region or an IL-17 receptor        A binding fragment thereof-encoding polynucleotide sequence        comprising SEQ ID NO:93;    -   l) a light chain CDR1-encoding polynucleotide comprising SEQ ID        NO:384, CDR2-encoding polynucleotide comprising SEQ ID NO:385,        CDR3-encoding polynucleotide comprising SEQ ID NO:386 and a        heavy chain CDR1-encoding polynucleotide comprising SEQ ID        NO:305, CDR2-encoding polynucleotide comprising SEQ ID NO:306,        CDR3-encoding polynucleotide comprising SEQ ID NO:307; and    -   m) a heavy chain CDR3-encoding polynucleotide comprising SEQ ID        NO:307 and a light chain CDR3-encoding polynucleotide comprising        SEQ ID NO:386.

Embodiment 71: the plasmid of embodiment 60, wherein the polynucleotideis the polynucleotide of embodiment 69. Embodiment 72: the isolated cellof embodiment 62, wherein the polynucleotide is the polynucleotide ofembodiment 69. Embodiment 73: the isolated cell of embodiment 65,wherein said expression vector comprises the polynucleotide ofembodiment 69. Embodiment 74: the isolated cell of embodiment 66,wherein the cell is a CHO cell and said CHO cell comprises thepolynucleotide of embodiment 69. Embodiment 75: the method according toembodiment 67, wherein the polynucleotide is the polynucleotide ofembodiment 69.

Nucleotide sequences corresponding to the amino acid sequences describedherein, to be used as probes or primers for the isolation of nucleicacids or as query sequences for database searches, can be obtained by“back-translation” from the amino acid sequences, or by identificationof regions of amino acid identity with polypeptides for which the codingDNA sequence has been identified. The well-known polymerase chainreaction (PCR) procedure can be employed to isolate and amplify a DNAsequence encoding a IL-17RA antigen binding proteins or a desiredcombination of IL-17RA antigen binding protein polypeptide fragments.Oligonucleotides that define the desired termini of the combination ofDNA fragments are employed as 5′ and 3′ primers. The oligonucleotidescan additionally contain recognition sites for restrictionendonucleases, to facilitate insertion of the amplified combination ofDNA fragments into an expression vector. PCR techniques are described inSaiki et al., Science 239:487 (1988); Recombinant DNA Methodology, Wu etal., eds., Academic Press, Inc., San Diego (1989), pp. 189-196; and PCRProtocols: A Guide to Methods and Applications, Innis et. al., eds.,Academic Press, Inc. (1990).

Nucleic acid molecules of the invention include DNA and RNA in bothsingle-stranded and double-stranded form, as well as the correspondingcomplementary sequences. DNA includes, for example, cDNA, genomic DNA,chemically synthesized DNA, DNA amplified by PCR, and combinationsthereof. The nucleic acid molecules of the invention include full-lengthgenes or cDNA molecules as well as a combination of fragments thereof.The nucleic acids of the invention are preferentially derived from humansources, but the invention includes those derived from non-humanspecies, as well.

An “isolated nucleic acid” is a nucleic acid that has been separatedfrom adjacent genetic sequences present in the genome of the organismfrom which the nucleic acid was isolated, in the case of nucleic acidsisolated from naturally-occurring sources. In the case of nucleic acidssynthesized enzymatically from a template or chemically, such as PCRproducts, cDNA molecules, or oligonucleotides for example, it isunderstood that the nucleic acids resulting from such processes areisolated nucleic acids. An isolated nucleic acid molecule refers to anucleic acid molecule in the form of a separate fragment or as acomponent of a larger nucleic acid construct. In one preferredembodiment, the nucleic acids are substantially free from contaminatingendogenous material. The nucleic acid molecule has preferably beenderived from DNA or RNA isolated at least once in substantially pureform and in a quantity or concentration enabling identification,manipulation, and recovery of its component nucleotide sequences bystandard biochemical methods (such as those outlined in Sambrook et al.,Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring HarborLaboratory, Cold Spring Harbor, N.Y. (1989)). Such sequences arepreferably provided and/or constructed in the form of an open readingframe uninterrupted by internal non-translated sequences, or introns,that are typically present in eukaryotic genes. Sequences ofnon-translated DNA can be present 5′ or 3′ from an open reading frame,where the same do not interfere with manipulation or expression of thecoding region.

The present invention also includes nucleic acids that hybridize undermoderately stringent conditions, and more preferably highly stringentconditions, to nucleic acids encoding IL-17RA antigen binding proteinsas described herein. The basic parameters affecting the choice ofhybridization conditions and guidance for devising suitable conditionsare set forth by Sambrook, Fritsch, and Maniatis (1989, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., chapters 9 and 11; and Current Protocols inMolecular Biology, 1995, Ausubel et al., eds., John Wiley & Sons, Inc.,sections 2.10 and 6.3-6.4), and can be readily determined by thosehaving ordinary skill in the art based on, for example, the lengthand/or base composition of the DNA. One way of achieving moderatelystringent conditions involves the use of a prewashing solutioncontaining 5×SSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0), hybridization bufferof about 50% formamide, 6×SSC, and a hybridization temperature of about55 degrees C. (or other similar hybridization solutions, such as onecontaining about 50% formamide, with a hybridization temperature ofabout 42 degrees C.), and washing conditions of about 60 degrees C., in0.5×SSC, 0.1% SDS. Generally, highly stringent conditions are defined ashybridization conditions as above, but with washing at approximately 68degrees C., 0.2×SSC, 0.1% SDS. SSPE (1×SSPE is 0.15M NaCl, 10 mMNaH.sub.2 PO.sub.4, and 1.25 mM EDTA, pH 7.4) can be substituted for SSC(1×SSC is 0.15M NaCl and 15 mM sodium citrate) in the hybridization andwash buffers; washes are performed for 15 minutes after hybridization iscomplete. It should be understood that the wash temperature and washsalt concentration can be adjusted as necessary to achieve a desireddegree of stringency by applying the basic principles that governhybridization reactions and duplex stability, as known to those skilledin the art and described further below (see, e.g., Sambrook et al.,1989). When hybridizing a nucleic acid to a target nucleic acid ofunknown sequence, the hybrid length is assumed to be that of thehybridizing nucleic acid. When nucleic acids of known sequence arehybridized, the hybrid length can be determined by aligning thesequences of the nucleic acids and identifying the region or regions ofoptimal sequence complementarity. The hybridization temperature forhybrids anticipated to be less than 50 base pairs in length should be 5to 10.degrees C. less than the melting temperature (Tm) of the hybrid,where Tm is determined according to the following equations. For hybridsless than 18 base pairs in length, Tm (degrees C.)=2(# of A+T bases)+4(#of #G+C bases). For hybrids above 18 base pairs in length, Tm (degreesC.)=81.5+16.6(log₁₀ [Na⁺])+0.41(% G+C)−(600/N), where N is the number ofbases in the hybrid, and [Na⁺] is the concentration of sodium ions inthe hybridization buffer ([Na⁺] for 1×SSC=0.165M). Preferably, each suchhybridizing nucleic acid has a length that is at least 15 nucleotides(or more preferably at least 18 nucleotides, or at least 20 nucleotides,or at least 25 nucleotides, or at least 30 nucleotides, or at least 40nucleotides, or most preferably at least 50 nucleotides), or at least25% (more preferably at least 50%, or at least 60%, or at least 70%, andmost preferably at least 80%) of the length of the nucleic acid of thepresent invention to which it hybridizes, and has at least 60% sequenceidentity (more preferably at least 70%, at least 75%, at least 80%, atleast 81%, at least 82%, at least 83%, at least 84%, at least 85%, atleast 86%, at least 87%, at least 88%, at least 89%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99%, and mostpreferably at least 99.5%) with the nucleic acid of the presentinvention to which it hybridizes, where sequence identity is determinedby comparing the sequences of the hybridizing nucleic acids when alignedso as to maximize overlap and identity while minimizing sequence gaps asdescribed in more detail above.

The variants according to the invention are ordinarily prepared by sitespecific mutagenesis of nucleotides in the DNA encoding the antigenbinding protein, using cassette or PCR mutagenesis or other techniqueswell known in the art, to produce DNA encoding the variant, andthereafter expressing the recombinant DNA in cell culture as outlinedherein. However, antigen binding protein fragments comprising variantCDRs having up to about 100-150 residues may be prepared by in vitrosynthesis using established techniques. The variants typically exhibitthe same qualitative biological activity as the naturally occurringanalogue, e.g., binding to IL-17RA and inhibiting signaling, althoughvariants can also be selected which have modified characteristics aswill be more fully outlined below.

As will be appreciated by those in the art, due to the degeneracy of thegenetic code, an extremely large number of nucleic acids may be made,all of which encode the CDRs (and heavy and light chains or othercomponents of the antigen binding protein) of the present invention.Thus, having identified a particular amino acid sequence, those skilledin the art could make any number of different nucleic acids, by simplymodifying the sequence of one or more codons in a way which does notchange the amino acid sequence of the encoded protein.

The present invention also provides expression systems and constructs inthe form of plasmids, expression vectors, transcription or expressioncassettes which comprise at least one polynucleotide as above. Inaddition, the invention provides host cells comprising such expressionsystems or constructs.

Typically, expression vectors used in any of the host cells will containsequences for plasmid maintenance and for cloning and expression ofexogenous nucleotide sequences. Such sequences, collectively referred toas “flanking sequences” in certain embodiments will typically includeone or more of the following nucleotide sequences: a promoter, one ormore enhancer sequences, an origin of replication, a transcriptionaltermination sequence, a complete intron sequence containing a donor andacceptor splice site, a sequence encoding a leader sequence forpolypeptide secretion, a ribosome binding site, a polyadenylationsequence, a polylinker region for inserting the nucleic acid encodingthe polypeptide to be expressed, and a selectable marker element. Eachof these sequences is discussed below.

Optionally, the vector may contain a “tag”-encoding sequence, i.e., anoligonucleotide molecule located at the 5′ or 3′ end of the IL-17RAantigen binding protein coding sequence; the oligonucleotide sequenceencodes polyHis (such as hexaHis), or another “tag” such as FLAG, HA(hemaglutinin influenza virus), or myc, for which commercially availableantibodies exist. This tag is typically fused to the polypeptide uponexpression of the polypeptide, and can serve as a means for affinitypurification or detection of the IL-17RA antigen binding protein fromthe host cell. Affinity purification can be accomplished, for example,by column chromatography using antibodies against the tag as an affinitymatrix. Optionally, the tag can subsequently be removed from thepurified IL-17RA antigen binding protein by various means such as usingcertain peptidases for cleavage.

Flanking sequences may be homologous (i.e., from the same species and/orstrain as the host cell), heterologous (i.e., from a species other thanthe host cell species or strain), hybrid (i.e., a combination offlanking sequences from more than one source), synthetic or native. Assuch, the source of a flanking sequence may be any prokaryotic oreukaryotic organism, any vertebrate or invertebrate organism, or anyplant, provided that the flanking sequence is functional in, and can beactivated by, the host cell machinery.

Flanking sequences useful in the vectors of this invention may beobtained by any of several methods well known in the art. Typically,flanking sequences useful herein will have been previously identified bymapping and/or by restriction endonuclease digestion and can thus beisolated from the proper tissue source using the appropriate restrictionendonucleases. In some cases, the full nucleotide sequence of a flankingsequence may be known. Here, the flanking sequence may be synthesizedusing the methods described herein for nucleic acid synthesis orcloning.

Whether all or only a portion of the flanking sequence is known, it maybe obtained using polymerase chain reaction (PCR) and/or by screening agenomic library with a suitable probe such as an oligonucleotide and/orflanking sequence fragment from the same or another species. Where theflanking sequence is not known, a fragment of DNA containing a flankingsequence may be isolated from a larger piece of DNA that may contain,for example, a coding sequence or even another gene or genes. Isolationmay be accomplished by restriction endonuclease digestion to produce theproper DNA fragment followed by isolation using agarose gelpurification, Qiagen® column chromatography (Chatsworth, Calif.), orother methods known to the skilled artisan. The selection of suitableenzymes to accomplish this purpose will be readily apparent to one ofordinary skill in the art.

An origin of replication is typically a part of those prokaryoticexpression vectors purchased commercially, and the origin aids in theamplification of the vector in a host cell. If the vector of choice doesnot contain an origin of replication site, one may be chemicallysynthesized based on a known sequence, and ligated into the vector. Forexample, the origin of replication from the plasmid pBR322 (New EnglandBiolabs, Beverly, Mass.) is suitable for most gram-negative bacteria,and various viral origins (e.g., SV40, polyoma, adenovirus, vesicularstomatitus virus (VSV), or papillomaviruses such as HPV or BPV) areuseful for cloning vectors in mammalian cells. Generally, the origin ofreplication component is not needed for mammalian expression vectors(for example, the SV40 origin is often used only because it alsocontains the virus early promoter).

A transcription termination sequence is typically located 3′ to the endof a polypeptide coding region and serves to terminate transcription.Usually, a transcription termination sequence in prokaryotic cells is aG-C rich fragment followed by a poly-T sequence. While the sequence iseasily cloned from a library or even purchased commercially as part of avector, it can also be readily synthesized using methods for nucleicacid synthesis such as those described herein.

A selectable marker gene encodes a protein necessary for the survivaland growth of a host cell grown in a selective culture medium. Typicalselection marker genes encode proteins that (a) confer resistance toantibiotics or other toxins, e.g., ampicillin, tetracycline, orkanamycin for prokaryotic host cells; (b) complement auxotrophicdeficiencies of the cell; or (c) supply critical nutrients not availablefrom complex or defined media. Specific selectable markers are thekanamycin resistance gene, the ampicillin resistance gene, and thetetracycline resistance gene. Advantageously, a neomycin resistance genemay also be used for selection in both prokaryotic and eukaryotic hostcells.

Other selectable genes may be used to amplify the gene that will beexpressed. Amplification is the process wherein genes that are requiredfor production of a protein critical for growth or cell survival arereiterated in tandem within the chromosomes of successive generations ofrecombinant cells. Examples of suitable selectable markers for mammaliancells include dihydrofolate reductase (DHFR) and promoterless thyrnidinekinase genes. Mammalian cell transformants are placed under selectionpressure wherein only the transformants are uniquely adapted to surviveby virtue of the selectable gene present in the vector. Selectionpressure is imposed by culturing the transformed cells under conditionsin which the concentration of selection agent in the medium issuccessively increased, thereby leading to the amplification of both theselectable gene and the DNA that encodes another gene, such as anantigen binding protein antibody that binds to IL-17RA polypeptide. As aresult, increased quantities of a polypeptide such as an IL-17RA antigenbinding protein are synthesized from the amplified DNA.

A ribosome-binding site is usually necessary for translation initiationof mRNA and is characterized by a Shine-Dalgarno sequence (prokaryotes)or a Kozak sequence (eukaryotes). The element is typically located 3′ tothe promoter and 5′ to the coding sequence of the polypeptide to beexpressed.

In some cases, such as where glycosylation is desired in a eukaryotichost cell expression system, one may manipulate the various pre- orprosequences to improve glycosylation or yield. For example, one mayalter the peptidase cleavage site of a particular signal peptide, or addprosequences, which also may affect glycosylation. The final proteinproduct may have, in the −1 position (relative to the first amino acidof the mature protein) one or more additional amino acids incident toexpression, which may not have been totally removed. For example, thefinal protein product may have one or two amino acid residues found inthe peptidase cleavage site, attached to the amino-terminus.Alternatively, use of some enzyme cleavage sites may result in aslightly truncated form of the desired polypeptide, if the enzyme cutsat such area within the mature polypeptide.

Expression and cloning vectors of the invention will typically contain apromoter that is recognized by the host organism and operably linked tothe molecule encoding the IL-17RA antigen binding protein. Promoters areuntranscribed sequences located upstream (i.e., 5′) to the start codonof a structural gene (generally within about 100 to 1000 bp) thatcontrol transcription of the structural gene. Promoters areconventionally grouped into one of two classes: inducible promoters andconstitutive promoters. Inducible promoters initiate increased levels oftranscription from DNA under their control in response to some change inculture conditions, such as the presence or absence of a nutrient or achange in temperature. Constitutive promoters, on the other hand,uniformly transcribe gene to which they are operably linked, that is,with little or no control over gene expression. A large number ofpromoters, recognized by a variety of potential host cells, are wellknown. A suitable promoter is operably linked to the DNA encoding heavychain or light chain comprising an IL-17RA antigen binding protein ofthe invention by removing the promoter from the source DNA byrestriction enzyme digestion and inserting the desired promoter sequenceinto the vector.

Suitable promoters for use with yeast hosts are also well known in theart. Yeast enhancers are advantageously used with yeast promoters.Suitable promoters for use with mammalian host cells are well known andinclude, but are not limited to, those obtained from the genomes ofviruses such as polyoma virus, fowlpox virus, adenovirus (such asAdenovirus 2), bovine papilloma virus, avian sarcoma virus,cytomegalovirus, retroviruses, hepatitis-B virus and most preferablySimian Virus 40 (SV40). Other suitable mammalian promoters includeheterologous mammalian promoters, for example, heat-shock promoters andthe actin promoter.

Additional promoters which may be of interest include, but are notlimited to: SV40 early promoter (Benoist and Chambon, 1981, Nature290:304-310); CMV promoter (Thornsen et al., 1984, Proc. Natl. Acad.U.S.A. 81:659-663); the promoter contained in the 3′ long terminalrepeat of Rous sarcoma virus (Yamamoto et al., 1980, Cell 22:787-797);herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad.Sci. U.S.A. 78:1444-1445); promoter and regulatory sequences from themetallothionine gene Prinster et al., 1982, Nature 296:39-42); andprokaryotic promoters such as the beta-lactamase promoter(Villa-Kamaroff et al., 1978, Proc. Natl. Acad. Sci. U.S.A.75:3727-3731); or the tac promoter (DeBoer et al., 1983, Proc. Natl.Acad. Sci. U.S.A. 80:21-25). Also of interest are the following animaltranscriptional control regions, which exhibit tissue specificity andhave been utilized in transgenic animals: the elastase I gene controlregion that is active in pancreatic acinar cells (Swift et al., 1984,Cell 38:639-646; Omitz et al., 1986, Cold Spring Harbor Symp. Quant.Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); the insulingene control region that is active in pancreatic beta cells (Hanahan,1985, Nature 315:115-122); the immunoglobulin gene control region thatis active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658;Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol.Cell. Biol. 7:1436-1444); the mouse mammary tumor virus control regionthat is active in testicular, breast, lymphoid and mast cells (Leder etal., 1986, Cell 45:485-495); the albumin gene control region that isactive in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276); thealpha-feto-protein gene control region that is active in liver (Krumlaufet al., 1985, Mol. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science253:53-58); the alpha 1-antitrypsin gene control region that is activein liver (Kelsey et al., 1987, Genes and Devel. 1: 161-171); thebeta-globin gene control region that is active in myeloid cells (Mogramet al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94);the myelin basic protein gene control region that is active inoligodendrocyte cells in the brain (Readhead et al., 1987, Cell48:703-712); the myosin light chain-2 gene control region that is activein skeletal muscle (Sani, 1985, Nature 314:283-286); and thegonadotropic releasing hormone gene control region that is active in thehypothalamus (Mason et al., 1986, Science 234:1372-1378).

An enhancer sequence may be inserted into the vector to increasetranscription of DNA encoding light chain or heavy chain comprising anIL-17RA antigen binding protein of the invention by higher eukaryotes.Enhancers are cis-acting elements of DNA, usually about 10-300 bp inlength, that act on the promoter to increase transcription. Enhancersare relatively orientation and position independent, having been foundat positions both 5′ and 3′ to the transcription unit. Several enhancersequences available from mammalian genes are known (e.g., globin,elastase, albumin, alpha-feto-protein and insulin). Typically, however,an enhancer from a virus is used. The SV40 enhancer, the cytomegalovirusearly promoter enhancer, the polyoma enhancer, and adenovirus enhancersknown in the art are exemplary enhancing elements for the activation ofeukaryotic promoters. While an enhancer may be positioned in the vectoreither 5′ or 3′ to a coding sequence, it is typically located at a site5′ from the promoter. A sequence encoding an appropriate native orheterologous signal sequence (leader sequence or signal peptide) can beincorporated into an expression vector, to promote extracellularsecretion of the antibody. The choice of signal peptide or leaderdepends on the type of host cells in which the antibody is to beproduced, and a heterologous signal sequence can replace the nativesignal sequence. Examples of signal peptides that are functional inmammalian host cells include the following: the signal sequence forinterleukin-7 (IL-7) described in U.S. Pat. No. 4,965,195; the signalsequence for interleukin-2 receptor described in Cosman et al., 1984,Nature 312:768; the interleukin-4 receptor signal peptide described inEP Patent No. 0367 566; the type I interleukin-1 receptor signal peptidedescribed in U.S. Pat. No. 4,968,607; the type II interleukin-1 receptorsignal peptide described in EP Patent No. 0 460 846.

Expression vectors of the invention may be constructed from a startingvector such as a commercially available vector. Such vectors may or maynot contain all of the desired flanking sequences. Where one or more ofthe flanking sequences described herein are not already present in thevector, they may be individually obtained and ligated into the vector.Methods used for obtaining each of the flanking sequences are well knownto one skilled in the art.

After the vector has been constructed and a nucleic acid moleculeencoding light chain, a heavy chain, or a light chain and a heavy chaincomprising an IL-17RA antigen binding sequence has been inserted intothe proper site of the vector, the completed vector may be inserted intoa suitable host cell for amplification and/or polypeptide expression.The transformation of an expression vector for an IL-17RA antigenbinding protein into a selected host cell may be accomplished by wellknown methods including transfection, infection, calcium phosphateco-precipitation, electroporation, microinjection, lipofection,DEAE-dextran mediated transfection, or other known techniques. Themethod selected will in part be a function of the type of host cell tobe used. These methods and other suitable methods are well known to theskilled artisan, and are set forth, for example, in Sambrook et al.,2001, supra.

A host cell, when cultured under appropriate conditions, synthesizes anIL-17RA antigen binding protein that can subsequently be collected fromthe culture medium (if the host cell secretes it into the medium) ordirectly from the host cell producing it (if it is not secreted). Theselection of an appropriate host cell will depend upon various factors,such as desired expression levels, polypeptide modifications that aredesirable or necessary for activity (such as glycosylation orphosphorylation) and ease of folding into a biologically activemolecule. A host cell may be eukaryotic or prokaryotic.

Mammalian cell lines available as hosts for expression are well known inthe art and include, but are not limited to, immortalized cell linesavailable from the American Type Culture Collection (ATCC) and any celllines used in an expression system known in the art can be used to makethe recombinant polypeptides of the invention. In general, host cellsare transformed with a recombinant expression vector that comprises DNAencoding a desired anti-IL-17RA antibody polypeptide. Among the hostcells that may be employed are prokaryotes, yeast or higher eukaryoticcells. Prokaryotes include gram negative or gram positive organisms, forexample E. coli or bacilli. Higher eukaryotic cells include insect cellsand established cell lines of mammalian origin. Examples of suitablemammalian host cell lines include the COS-7 line of monkey kidney cells(ATCC CRL 1651) (Gluzman et al., 1981, Cell 23:175), L cells, 293 cells,C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells,or their derivatives such as Veggie CHO and related cell lines whichgrow in serum-free media (Rasmussen et al., 1998, Cytotechnology 28:31), HeLa cells, BHK (ATCC CRL 10) cell lines, and the CVI/EBNA cellline derived from the African green monkey kidney cell line CVI (ATCCCCL 70) as described by McMahan et al., 1991, EMBO J. 10: 2821, humanembryonic kidney cells such as 293, 293 EBNA or MSR 293, human epidermalA431 cells, human Colo205 cells, other transformed primate cell lines,normal diploid cells, cell strains derived from in vitro culture ofprimary tissue, primary explants, HL-60, U937, HaK or Jurkat cells.Optionally, mammalian cell lines such as HepG2/3B, KB, NIH 3T3 or S49,for example, can be used for expression of the polypeptide when it isdesirable to use the polypeptide in various signal transduction orreporter assays. Alternatively, it is possible to produce thepolypeptide in lower eukaryotes such as yeast or in prokaryotes such asbacteria. Suitable yeasts include Saccharomyces cerevisiae,Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeaststrain capable of expressing heterologous polypeptides. Suitablebacterial strains include Escherichia coli, Bacillus subtilis,Salmonella typhimurium, or any bacterial strain capable of expressingheterologous polypeptides. If the polypeptide is made in yeast orbacteria, it may be desirable to modify the polypeptide producedtherein, for example by phosphorylation or glycosylation of theappropriate sites, in order to obtain the functional polypeptide. Suchcovalent attachments can be accomplished using known chemical orenzymatic methods. The polypeptide can also be produced by operablylinking the isolated nucleic acid of the invention to suitable controlsequences in one or more insect expression vectors, and employing aninsect expression system. Materials and Methods for baculovirus/insectcell expression systems are commercially available in kit form from,e.g., Invitrogen, San Diego, Calif., U.S.A. (the MaxBac® kit), and suchmethods are well known in the art, as described in Summers and Smith,Texas Agricultural Experiment Station Bulletin No. 1555 (1987), andLuckow and Summers, Bio/Technology 6:47 (1988). Cell-free translationsystems could also be employed to produce polypeptides using RNAsderived from nucleic acid constructs disclosed herein. Appropriatecloning and expression vectors for use with bacterial, fungal, yeast,and mammalian cellular hosts are described by Pouwels et al. (CloningVectors: A Laboratory Manual, Elsevier, New York, 1985). A host cellthat comprises an isolated nucleic acid of the invention, preferablyoperably linked to at least one expression control sequence, is a“recombinant host cell”.

In certain embodiments, cell lines may be selected through determiningwhich cell lines have high expression levels and constitutively produceantigen binding proteins with IL-17RA binding properties. In anotherembodiment, a cell line from the B cell lineage that does not make itsown antibody but has a capacity to make and secrete a heterologousantibody can be selected.

Identification of Domains on Human IL-17RA that Neutralizing AntibodiesBound

Examples 14-17 describe various studies elucidating domains on humanIL-17RA that neutralizing IL-17RA mAbs bound. These domains are referredto as neutralizing determinants. A neutralizing determinant is acontiguous stretch of IL-17RA, that when mutated, negatively affects thebinding of at least one of the neutralizing antibodies disclosed herein.A neutralizing determinant comprises at least one epitope. Aneutralizing determinant may have primary, secondary, teriary, and/orquarternary structural characteristics. A neutralizing antibody is anyof the antibodies described herein that specifically binds human IL-17RAand inhibits binding of IL-17A and/or IL-17F and thereby inhibitsIL-17RA signaling and/or biological activity. Examples of neutralizingantibodies include antibodies comprising AM_(L)1/AM_(H)1 (SEQ IDNO:27/SEQ ID NO:1), AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2),AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3), AM_(L)4/AM_(H)4 (SEQ IDNO:30/SEQ ID NO:4), AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5),AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6), AM_(L)7/AM_(H)7 (SEQ IDNO:33/SEQ ID NO:7), AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8),AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9), AM_(L)10/AM_(H)10 (SEQ IDNO:36/SEQ ID NO:10), AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11),AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12), AM_(L)13/AM_(H)13 (SEQ IDNO:39/SEQ ID NO:13), AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14),AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15), AM_(L)16/AM_(H)16 (SEQ IDNO:42/SEQ ID NO:16), AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17),AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18), AM_(L)19/AM_(H)19 (SEQ IDNO:45/SEQ ID NO:19), AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20),AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21), AM_(L)22/AM_(H)22 (SEQ IDNO:48/SEQ ID NO:22), AM_(L)23/AM_(H)23 (SEQ ID NO:49 or SEQ ID NO:50/SEQID NO:23), AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24),AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25), AM_(L)26/AM_(H)26 (SEQ IDNO:53/SEQ ID NO:26), as well as IL-17RA-binding fragments thereof andcombinations thereof.

Further embodiments of neutralizing antibodies include antibodies thatspecifically bind to human IL-17RA and inhibit IL-17A and/or IL-17F frombinding and activating IL-17RA, or a heteromeric complex of IL-17RA andIL-17RC. Further embodiments include antibodies that specifically bindto human IL-17RA and inhibit an IL-17A/IL-17F heteromer from binding andactivating IL-17RA, or a heteromeric complex of IL-17RA and IL-17RC.Further embodiments include antibodies that specifically bind to humanIL-17RA and partially or fully inhibit IL-17RA from forming either ahomomeric or heteromeric functional receptor complex, such as, but notlimited to IL-17RA-IL-17RC complex. Further embodiments includeantibodies that specifically bind to human IL-17RA and partially orfully inhibit IL-17RA from forming either a homomeric or heteromericfunctional receptor complex, such as, but not limited to IL-17RA/IL-17RCcomplex and do not necessarily inhibit IL-17A and/or IL-17F or anIL-17A/IL-17F heteromer from binding to IL-17RA or a IL-17RA heteromericreceptor complex.

Further examples of neutralizing antibodies include antibodiescomprising at least one CDR from antibodies comprising AM_(L)1/AM_(H)1(SEQ ID NO:27/SEQ ID NO:1), AM_(L)2/AM_(H)2 (SEQ ID NO:28/SEQ ID NO:2),AM_(L)3/AM_(H)3 (SEQ ID NO:29/SEQ ID NO:3), AM_(L)4/AM_(H)4 (SEQ IDNO:30/SEQ ID NO:4), AM_(L)5/AM_(H)5 (SEQ ID NO:31/SEQ ID NO:5),AM_(L)6/AM_(H)6 (SEQ ID NO:32/SEQ ID NO:6), AM_(L)7/AM_(H)7 (SEQ IDNO:33/SEQ ID NO:7), AM_(L)8/AM_(H)8 (SEQ ID NO:34/SEQ ID NO:8),AM_(L)9/AM_(H)9 (SEQ ID NO:35/SEQ ID NO:9), AM_(L)10/AM_(H)10 (SEQ IDNO:36/SEQ ID NO:10), AM_(L)11/AM_(H)11 (SEQ ID NO:37/SEQ ID NO:11),AM_(L)12/AM_(H)12 (SEQ ID NO:38/SEQ ID NO:12), AM_(L)13/AM_(H)13 (SEQ IDNO:39/SEQ ID NO:13), AM_(L)14/AM_(H)14 (SEQ ID NO:40/SEQ ID NO:14),AM_(L)15/AM_(H)15 (SEQ ID NO:41/SEQ ID NO:15), AM_(L)16/AM_(H)16 (SEQ IDNO:42/SEQ ID NO:16), AM_(L)17/AM_(H)17 (SEQ ID NO:43/SEQ ID NO:17),AM_(L)18/AM_(H)18 (SEQ ID NO:44/SEQ ID NO:18), AM_(L)19/AM_(H)19 (SEQ IDNO:45/SEQ ID NO:19), AM_(L)20/AM_(H)20 (SEQ ID NO:46/SEQ ID NO:20),AM_(L)21/AM_(H)21 (SEQ ID NO:47/SEQ ID NO:21), AM_(L)22/AM_(H)22 (SEQ IDNO:48/SEQ ID NO:22), AM_(L)23/AM_(H)23 (SEQ ID NO:49 or SEQ ID NO:50/SEQID NO:23), AM_(L)24/AM_(H)24 (SEQ ID NO:51/SEQ ID NO:24),AM_(L)25/AM_(H)25 (SEQ ID NO:52/SEQ ID NO:25), AM_(L)26/AM_(H)26 (SEQ IDNO:53/SEQ ID NO:26), as well as L-17RA-binding fragments thereof andcombinations thereof. See Table 1.

FIGS. 16A and 16B show that antibodies A: AM_(H)11/AM_(L)11, B:AM_(H)4/AM_(L)4, C: AM_(H)8/AM_(L)8, D: AM_(H)7/AM_(L)7, E:AM_(H)6/AM_(L)6, F: AM_(H)10/AM_(L)10, and G: AM_(H)18/AM_(L)18 competedwith one another for binding to human IL-17RA and fell into a definedgroup (Bin 1). In general, antibodies 1: AM_(H)22/AM_(L)22, J:AM_(H)23/AM_(L)23, K: AM_(H)14/AM_(L)14, L: AM_(H)19/AM_(L)19, M:AM_(H)12/AM_(L)12, N: AM_(H)17/AM_(L)17, O: AM_(H)16/AM_(L)16 competedwith one another for binding to human IL-17RA and as a consequence fellinto a different group (Bin 3). Generally speaking, the antibodies ofBin 1 did not compete with the antibodies of Bin 3. Antibody H:AM_(H)1/AM_(L)1 was unique in its competition pattern and formed Bin 2,but is most similar to Bin 3. Antibody P: AM_(H)26/AM_(L)26 formed Bin 4and showed little cross-competition with any of the other antibodies,suggesting a neutralizing determinant unique to this antibody.Antibodies Q: AM_(H)21/AM_(L)21 and R: AM_(H)20/AM_(L)20 showedindividually unique competition patterns, but with considerablesimilarities to Bin 3 antibodies, and formed Bins 5 and 6, respectively.This method identified groups of antibodies binding to differentneutralizing determinants and provides evidence of several specieswithin a subgenus of cross-competing antibodies.

Example 16 describes the use of human/mouse IL-17RA chimeric proteins todetermine neutralizing determinants on human IL-17RA. FIG. 19 show thatat least three neutralizing determinants were identified based on thoseregions affecting the binding of neutralizing IL-17RA antibodies, namelyDomain B spanning amino acids 75-96 of human IL-17RA (SEQ ID NO:431),Domain C spanning amino acids 128-154 of human IL-17RA (SEQ ID NO:431),and Domain D spanning amino acids 176-197 of human IL-17RA (SEQ IDNO:431). Domain B spanning amino acids 75-96 of human IL-17RA (SEQ IDNO:431) negatively affected the binding of neutralizing antibodiesAM_(H)1/AM_(L)1 and AM_(H)23/AM_(L)23. Domain C spanning amino acids128-154 of human IL-17RA (SEQ ID NO:431) negatively affected the bindingof neutralizing antibodies AM_(H)22/AM_(L)22 and AM_(H)23/AM_(L)23.Domain D spanning amino acids 176-197 of human IL-17RA (SEQ ID NO:431)negatively affected the binding of neutralizing antibodiesAM_(H)1/AM_(L)1, AM_(H)22/AM_(L)22, AM_(H)14/AM_(L)14,AM_(H)19/AM_(L)19, AM_(H)23/AM_(L)23, AM_(H)21/AM_(L)21, andAM_(H)20/AM_(L)20. Thus, Domains B, C, and D are considered neutralizingdeterminants.

Example 17 describes the use of arginine scan techniques to furtherelucidate the domains on human IL-17R that the IL-17RA neutralizingantibodies bound. A summary of the arginine scan, binding, and chimeradata is presented in FIG. 22. The arginine scan methodology identifiedseveral neutralizing determinants: AM_(H)18/AM_(L)18 bound a domainspanning amino acids 220-284 of human IL-17RA (SEQ ID NO:431);AM_(H)1/AM_(L)1 bound a domain focused on amino acid residue 152 ofhuman IL-17RA (SEQ ID NO:431); AM_(H)22/AM_(L)22 bound a domain spanningamino acids 152-198 of human IL-17RA (SEQ ID NO:431); AM_(H)14/AM_(L)14bound a domain spanning amino acids 152-297 of human IL-17RA (SEQ IDNO:431); AM_(H)19/AM_(L)19 bound a domain spanning amino acids 152-186of human IL-17RA (SEQ ID NO:431); AM_(H)23/AM_(L)23 bound a domainspanning amino acids 97-297 of human IL-17RA (SEQ ID NO:431);AM_(H)26/AM_(L)26 bound a domain spanning amino acids 138-270 of humanIL-17RA (SEQ ID NO:431); AM_(H)21/AM_(L)21 bound a domain spanning aminoacids 113-198 of human IL-17RA (SEQ ID NO:431); and AM_(H)20/AM_(L)20bound a domain spanning amino acids 152-270 of human IL-17RA (SEQ IDNO:431). All of the residues shown in FIG. 22 have been shown tosignificantly reduce or essentially eliminate binding of a neutralizinghuman monoclonal antibody that specifically binds to human IL-17RA.

Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds to IL-17RA and competes for binding with any oneof antibodies AM_(H)3/AM_(L)3, AM_(H)20/AM_(L)20, AM_(H)22/AM_(L)22,AM_(H)23/AM_(L)23, AM_(H)14/AM_(L)14, AM_(H)21/AM_(L)21,AM_(H)19/AM_(L)19, AM_(H)12/AM_(L)12, AM_(H)17/AM_(L)17, orAM_(H)16/AM_(L)16, or any subset therein.

Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds to IL-17R and competes for binding with any oneof antibodies AM_(H)22/AM_(L)22, AM_(H)23/AM_(L)23, AM_(H)14/AM_(L)14,AM_(H)19/AM_(L)19, AM_(H)12/AM_(L)12, AM_(H)17/AM_(L)17, orAM_(H)16/AM_(L)16, or any subset therein.

Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds human IL-17RA of SEQ ID NO:431 but does notspecifically bind to a chimeric polypeptide consisting of SEQ ID NO:434.Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds human IL-17RA of SEQ ID NO:431 but does notspecifically bind to a chimeric polypeptide consisting of SEQ ID NO:435.Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds human IL-17RA of SEQ ID NO:431 but does notspecifically bind to a chimeric polypeptide consisting of SEQ ID NO:436.

Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds a neutralizing determinant comprising aminoacids 75-96 of SEQ ID NO:431 of human IL-17RA. Embodiments include anantibody, or IL-17RA-binding fragment thereof, that specifically binds aneutralizing determinant comprising amino acids 128-154 of SEQ ID NO:431of human IL-17RA. Embodiments include an antibody, or IL-17RA-bindingfragment thereof, that specifically binds a neutralizing determinantcomprising amino acids 176-197 of SEQ ID NO:431 of human IL-17RA.Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds a neutralizing determinant comprising aminoacids 152-297 of SEQ ID NO:431 of human IL-17RA. Embodiments include anantibody, or IL-17RA-binding fragment thereof, that specifically binds aneutralizing determinant comprising amino acids 220-284 of SEQ ID NO:431of human IL-17RA. Embodiments include an antibody, or IL-17RA-bindingfragment thereof, that specifically binds a neutralizing determinantcomprising amino acids 152-198 of SEQ ID NO:431 of human IL-17RA.Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds a neutralizing determinant comprising aminoacids 152-186 of SEQ ID NO:431 of human IL-17RA. Embodiments include anantibody, or IL-17RA-binding fragment thereof, that specifically binds aneutralizing determinant comprising amino acids 97-297 of SEQ ID NO:431of human IL-17RA. Embodiments include an antibody, or IL-17RA-bindingfragment thereof, that specifically binds a neutralizing determinantcomprising amino acids 138-270 of SEQ ID NO:431 of human IL-17RA.Embodiments include an antibody, or IL-17RA-binding fragment thereof,that specifically binds a neutralizing determinant comprising aminoacids 113-198 of SEQ ID NO:431 of human IL-17RA. Embodiments include anantibody, or IL-17RA-binding fragment thereof, that specifically binds aneutralizing determinant comprising amino acids 152-270 of SEQ ID NO:431of human IL-17RA.

Further embodiments include an antibody, or IL-17RA-binding fragmentthereof, that binds human IL-17RA of SEQ ID NO:431, but does not bindsaid IL-17RA having an amino acid substituted with arginine at any oneof E97R, E113R, S115R, H138R, D152R, D154R, E156R, K166R, Q176R, S177R,D184R, E186R, S198R, H215R, S220R, T228R, T235R, E241R, H243R, L270R,Q284R, H297R of SEQ ID NO:431. Embodiments include an antibody, orIL-17RA-binding fragment thereof, that binds human IL-17RA of SEQ IDNO:431, but does not bind said IL-17RA having an amino acid substitutedwith arginine at any one of D152R, D154R, E156R, D184R, E186R, H297R ofSEQ ID NO:431. Embodiments include an antibody, or IL-17RA-bindingfragment thereof, that binds human IL-17RA of SEQ ID NO:431, but doesnot bind said IL-17RA having an amino acid substituted with arginine atD152R of SEQ ID NO:431.

Further embodiments include an antibody, or IL-17RA-binding fragmentthereof, that specifically binds an epitope defined by any one of aminoacids D152, D154, E156, D184, E186, H297 of SEQ ID NO:431. Embodimentsinclude an antibody, or IL-17RA-binding fragment thereof, thatspecifically binds an epitope defined by at least two amino acidsselected from the group consisting of: D152, D154, E156, D184, E186,H297 of SEQ ID NO:431. Embodiments include an antibody, orIL-17RA-binding fragment thereof, that specifically binds an epitopedefined by at least three amino acids selected from the group consistingof: D152, D154, E156, D184, E186, H297 of SEQ ID NO:431. Embodimentsinclude an antibody, or IL-17RA-binding fragment thereof, thatspecifically binds an epitope defined by at least four amino acidsselected from the group consisting of: D152, D154, E156, D184, E186,H297 of SEQ ID NO:431. Embodiments include an antibody, orIL-17RA-binding fragment thereof, that specifically binds an epitopedefined by at least five amino acids selected from the group consistingof: D152, D154, E156, D184, E186, H297 of SEQ ID NO:431. Embodimentsinclude an antibody, or IL-17RA-binding fragment thereof, thatspecifically binds an epitope defined by amino acids D152, D154, E156,D184, E186, H297 of SEQ ID NO:431.

Use of IL-17RA Antigen Binding Proteins for Diagnostic and TherapeuticPurposes

The IL-17RA antigen binding proteins of the invention can be used indiagnostic assays, e.g., binding assays to detect and/or quantifyIL-17RA expressed in a tissue or cell. The IL-17RA antigen bindingproteins may be used in research to further investigate the role ofIL-17RA in disease. The IL-17RA antigen binding proteins may be used tofurther investigate the role of IL-17RA in forming homomeric and/orheteromeric receptor complexes and the role of said complexes indisease. The IL-17RA antigen binding proteins may be used to furtherinvestigate the role of IL-17RA activation to homomeric and/orheteromeric IL-17 ligand complexes. The IL-17RA antigen binding proteinsmay be used to further investigate the role of IL-17RA activation tohomomeric and/or heteromeric IL-17 ligand complexes and how saidhomomeric and/or heteromeric IL-17 ligand complexes relate to disease.

The IL-17RA antigen binding proteins of the present invention can beused for the prevention or treatment of diseases or conditionsassociated with the IL-17A and/or IL-17F activity. A disease orcondition associated with IL-17A and/or IL-17F means any disease,condition, or pathology whose onset in a patient is caused orexacerbated by the interaction of IL-17A and/or IL-17F with IL-17RA. Theseverity of the disease, condition, or pathology can also be increasedor decreased by the modulating the interaction of IL-17A and/or IL-17Fwith IL-17RA or a heterologous complex comprising IL-17RA and IL-17RC.

Antigen binding proteins of the invention that specifically bind toIL-17RA may be used in treatment of IL-17RA mediated diseases in apatient in need thereof. All aspects of the IL-17RA antigen bindingproteins described throughout this specification may be used in thepreparation of a medicament for the treatment of the various conditionsand diseases described herein. In addition, the IL-17RA antigen bindingprotein of the invention can be used to inhibit IL-17RA from forming acomplex with its ligand, e.g., IL-17A and/or IL-17F or any other IL-17ligand family member that binds IL-17RA or a heterologous complexcomprising IL-17RA and IL-17RC, thereby modulating the biologicalactivity of IL-17RA in a cell or tissue. Antigen binding proteins thatbind to IL-17RA thus may modulate and/or inhibit interaction with otherbinding compounds and as such may have therapeutic use in amelioratingIL-17RA mediated diseases. In specific embodiments, IL-17RA antigenbinding proteins may inhibit IL-17A and/or IL-17F from binding IL-17RA,which may result in disruption of the IL-17RA-induced signaltransduction cascade.

Increased levels of IL-17A and/or involvement of IL-17A mediated signalsin disease pathogenesis have been demonstrated in a variety ofconditions and diseases. Kolls and Linden, 2004, supra; Miossec, 2003,P. Arthritis Rheum. 48:594-601); WO2005/063290; Cannetti et al., 2003,J. Immunol. 171:1009-1015; Charles et al., 1999, J. Immunol. 163:1521-1528; Cunnane et al., 2000, Online J. Rheumatol. 27:58-63;Yoshimoto, 1998, J. Immunol. 161: 3400-3407), (WO2005/063290),(Niederau, 1997, Online NLM), (WO2004/002519), (Tsutsui et al., 2000,supra), (Konishi et al., 2002, Proc. Natl. Acad. Sci. U.S.A.99:11340-11345), Ziolkowska et al., 2000, supra). (Chabaud, 2001, Arth &Rheumatism, 44:1293). Thus, IL-17RA is said to influence the pathologyof these and other diseases or conditions described herein.

As described herein, a surrogate rat anti-mouse IL-17RA antibodyinhibits the course of disease and reduces bone and cartilagedegradation in both a prophylactic and therapeutic rodent collageninduced arthritis model (see Examples below). As further evidence of theefficacy of interrupting the IL-17A/IL-17RA pathway, IL-17RA knockoutmice are resistant to collagen-induced arthritis and IL-17RA antibodytreatment is effective in arthritis induced in TNFR knockout mice,showing a TNF independent effect (see Example 6).

Inhibiting IL-17RA using the antigen binding proteins disclosed hereinrepresents a novel and effective mechanism to inhibit the symptoms andpathology of inflammatory and autoimmune diseases, and in particularinflammation and joint degradation found in rheumatoid arthritis (RA),Preclinical data and data from RA patient tissues suggest the potentialto provide efficacy in those who failed TNF inhibitor therapy and toconfer added benefit in combination with TNF inhibitors, IL-6inhibitors, and IL-1 inhibitors.

The antigen binding proteins described herein may be used in combination(pre-treatment, post-treatment, or concurrent treatment) with any of oneor more TNF inhibitors for the treatment or prevention of the diseasesand disorders recited herein, such as but not limited to, all forms ofsoluble TNF receptors including Etanercept (such as ENBREL®), as well asall forms of monomeric or multimeric p75 and/or p55 TNF receptormolecules and fragments thereof; anti-human TNF antibodies, such as butnot limited to, Infliximab (such as REMICADE®), and D2E7 (such asHUMIRA®), and the like. Such TNF inhibitors include compounds andproteins which block in vivo synthesis or extracellular release of TNF.In a specific embodiment, the present invention is directed to the useof an IL-17RA antigen binding protein in combination (pre-treatment,post-treatment, or concurrent treatment) with any of one or more of thefollowing TNF inhibitors: TNF binding proteins (soluble TNF receptortype-I and soluble TNF receptor type-II (“sTNFRs”), as defined herein),anti-TNF antibodies, granulocyte colony stimulating factor; thalidomide;BN 50730; tenidap; E 5531; tiapafant PCA 4248; nimesulide; PANAVIR®(Probucol); rolipram; RP 73401; peptide T; MDL 201,449A;(1R,3S)-Cis-1-[9-(2,6-diaminopurinyl)]-3-hydroxy-4-cyclopentenehydrochloride;(1R,3R)-trans-1-(9-(2,6-diamino)purine]-3-acetoxycyclopentane;(1R,3R)-trans-1-[9-adenyl)-3-azidocyclopentane hydrochloride and(1R,3R)-trans-1-(6-hydroxy-purin-9-yl)-3-azidocyclo-pentane. TNF bindingproteins are disclosed in the art (EP 308 378, EP 422 339, GB 2 218 101,EP 393 438, WO 90/13575, EP 398 327, EP 412 486, WO 91/03553, EP 418014, JP 127,800/1991, EP 433 900, U.S. Pat. No. 5,136,021, GB 2 246 569,EP 464 533, WO 92/01002, WO 92/13095, WO 92/16221, EP 512 528, EP 526905, WO 93/07863, EP 568 928, WO 93/21946, WO 93/19777, EP 417 563, WO94/06476, and PCT International Application No. PCT/US97/12244).

For example, EP 393 438 and EP 422 339 teach the amino acid and nucleicacid sequences of a soluble TNF receptor type I (also known as “sTNFR-I”or “30 kDa TNF inhibitor”) and a soluble TNF receptor type II (alsoknown as “sTNFR-II” or “40 kDa TNF inhibitor”), collectively termed“sTNFRs”, as well as modified forms thereof (e.g., fragments, functionalderivatives and variants). EP 393 438 and EP 422 339 also disclosemethods for isolating the genes responsible for coding the inhibitors,cloning the gene in suitable vectors and cell types and expressing thegene to produce the inhibitors. Additionally, polyvalent forms (i.e.,molecules comprising more than one active moiety) of sTNFR-I andsTNFR-II have also been disclosed. In one embodiment, the polyvalentform may be constructed by chemically coupling at least one TNFinhibitor and another moiety with any clinically acceptable linker, forexample polyethylene glycol (WO 92/16221 and WO 95/34326), by a peptidelinker (Neve et al. (1996), Cytokine, 8(5):365-370, by chemicallycoupling to biotin and then binding to avidin (WO 91/03553) and,finally, by combining chimeric antibody molecules (U.S. Pat. No.5,116,964, WO 89/09622, WO 91/16437 and EP 315062.

Anti-TNF antibodies include the MAK 195F Fab antibody (Holler et al.(1993), 1st International Symposium on Cytokines in Bone MarrowTransplantation, 147); CDP 571 anti-TNF monoclonal antibody (Rankin etal. (1995), British Journal of Rheumatology, 34:334-342); BAY X 1351murine anti-tumor necrosis factor monoclonal antibody (Kieft et al.(1995), 7th European Congress of Clinical Microbiology and InfectiousDiseases, page 9); CenTNF cA2 anti-TNF monoclonal antibody (Elliott etal. (1994), Lancet, 344:1125-1127 and Elliott et al. (1994), Lancet,344:1105-1110).

The antigen binding proteins described herein may be used in combinationwith all forms of IL-1 inhibitors, such as but not limited to, kineret(for example ANAKINRA®). Interleukin-1 receptor antagonist (IL-1ra) is ahuman protein that acts as a natural inhibitor of interleukin-1.Interleukin-1 receptor antagonists, as well as the methods of making andmethods of using thereof, are described in U.S. Pat. No. 5,075,222; WO91/08285; WO 91/17184; AU 9173636; WO 92/16221; WO 93/21946; WO94/06457; WO 94/21275; FR 2706772; WO 94/21235; DE 4219626; WO 94/20517;WO 96/22793 and WO 97/28828. The proteins include glycosylated as wellas non-glycosylated IL-1 receptor antagonists. Specifically, threepreferred forms of IL-1ra (IL-1raα, IL-1raβ and IL-1rax), each beingencoded by the same DNA coding sequence and variants thereof, aredisclosed and described in U.S. Pat. No. 5,075,222. Methods forproducing IL-1 inhibitors, particularly IL-1ras, are also disclosed inthe U.S. Pat. No. 5,075,222. An additional class of interleukin-1inhibitors includes compounds capable of specifically preventingactivation of cellular receptors to IL-1. Such compounds include IL-1binding proteins, such as soluble receptors and monoclonal antibodies.Such compounds also include monoclonal antibodies to the receptors. Afurther class of interleukin-1 inhibitors includes compounds andproteins that block in vivo synthesis and/or extracellular release ofIL-1. Such compounds include agents that affect transcription of IL-1genes or processing of IL-1 preproteins.

The antigen binding proteins described herein may be used in combinationwith all forms of CD28 inhibitors, such as but not limited to, abatacept(for example ORENCIA®).

The antigen binding proteins described herein may be used in combinationwith all forms of IL-6 and/or IL-6 receptor inhibitors, such as but notlimited to, tocilizumab (for example ACTEMRA®).

The antigen binding proteins may be used in combination with one or morecytokines, lymphokines, hematopoietic factor(s), and/or ananti-inflammatory agent.

Treatment of the diseases and disorders recited herein can include theuse of first line drugs for control of pain and inflammation incombination (pretreatment, post-treatment, or concurrent treatment) withtreatment with one or more of the antigen binding proteins providedherein. These drugs are classified as non-steroidal, anti-inflammatorydrugs (NSAIDs). Secondary treatments include corticosteroids, slowacting antirheumatic drugs (SAARDs), or disease modifying (DM) drugs.Information regarding the following compounds can be found in The MerckManual of Diagnosis and Therapy, Sixteenth Edition, Merck, Sharp & DohmeResearch Laboratories, Merck & Co., Rahway, N.J. (1992) and inPharmaprojects, PJB Publications Ltd.

In a specific embodiment, the present invention is directed to the useof an antigen binding protein and any of one or more NSAIDs for thetreatment of the diseases and disorders recited herein. NSAIDs owe theiranti-inflammatory action, at least in part, to the inhibition ofprostaglandin synthesis (Goodman and Gilman in “The PharmacologicalBasis of Therapeutics,” MacMillan 7th Edition (1985)). NSAIDs can becharacterized into at least nine groups: (1) salicylic acid derivatives;(2) propionic acid derivatives; (3) acetic acid derivatives; (4) fenamicacid derivatives; (5) carboxylic acid derivatives; (6) butyric acidderivatives; (7) oxicams; (8) pyrazoles and (9) pyrazolones.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or moresalicylic acid derivatives, prodrug esters or pharmaceuticallyacceptable salts thereof. Such salicylic acid derivatives, prodrugesters and pharmaceutically acceptable salts thereof comprise:acetaminosalol, aloxiprin, aspirin, benorylate, bromosaligenin, calciumacetylsalicylate, choline magnesium trisalicylate, magnesium salicylate,choline salicylate, diflusinal, etersalate, fendosal, gentisic acid,glycol salicylate, imidazole salicylate, lysine acetylsalicylate,mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine,parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide,salicylamide O-acetic acid, salsalate, sodium salicylate andsulfasalazine. Structurally related salicylic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe encompassed by this group.

In an additional specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or morepropionic acid derivatives, prodrug esters or pharmaceuticallyacceptable salts thereof. The propionic acid derivatives, prodrugesters, and pharmaceutically acceptable salts thereof comprise:alminoprofen, benoxaprofen, bucloxic acid, carprofen, dexindoprofen,fenoprofen, flunoxaprofen, fluprofen, flurbiprofen, furcloprofen,ibuprofen, ibuprofen aluminum, ibuproxam, indoprofen, isoprofen,ketoprofen, loxoprofen, miroprofen, naproxen, naproxen sodium,oxaprozin, piketoprofen, pimeprofen, pirprofen, pranoprofen, protizinicacid, pyridoxiprofen, suprofen, tiaprofenic acid and tioxaprofen.Structurally related propionic acid derivatives having similar analgesicand anti-inflammatory properties are also intended to be encompassed bythis group.

In yet another specific embodiment, the present invention is directed tothe use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or more aceticacid derivatives, prodrug esters or pharmaceutically acceptable saltsthereof. The acetic acid derivatives, prodrug esters, andpharmaceutically acceptable salts thereof comprise: acemetacin,alclofenac, amfenac, bufexamac, cinmetacin, clopirac, delmetacin,diclofenac potassium, diclofenac sodium, etodolac, felbinac,fenclofenac, fenclorac, fenclozic acid, fentiazac, furofenac,glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac,metiazinic acid, oxametacin, oxpinac, pimetacin, proglumetacin,sulindac, talmetacin, tiaramide, tiopinac, tolmetin, tolmetin sodium,zidometacin and zomepirac. Structurally related acetic acid derivativeshaving similar analgesic and anti-inflammatory properties are alsointended to be encompassed by this group.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or more fenamicacid derivatives, prodrug esters or pharmaceutically acceptable saltsthereof. The fenamic acid derivatives, prodrug esters andpharmaceutically acceptable salts thereof comprise: enfenamic acid,etofenamate, flufenamic acid, isonixin, meclofenamic acid, meclofenamatesodium, medofenamic acid, mefenamic acid, niflumic acid, talniflumate,terofenamate, tolfenamic acid and ufenamate. Structurally relatedfenamic acid derivatives having similar analgesic and anti-inflammatoryproperties are also intended to be encompassed by this group.

In an additional specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or morecarboxylic acid derivatives, prodrug esters or pharmaceuticallyacceptable salts thereof. The carboxylic acid derivatives, prodrugesters, and pharmaceutically acceptable salts thereof which can be usedcomprise: clidanac, diflunisal, flufenisal, inoridine, ketorolac andtinoridine. Structurally related carboxylic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe encompassed by this group.

In yet another specific embodiment, the present invention is directed tothe use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or more butyricacid derivatives, prodrug esters or pharmaceutically acceptable saltsthereof. The butyric acid derivatives, prodrug esters, andpharmaceutically acceptable salts thereof comprise: bumadizon,butibufen, fenbufen and xenbucin. Structurally related butyric acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or moreoxicams, prodrug esters, or pharmaceutically acceptable salts thereof.The oxicams, prodrug esters, and pharmaceutically acceptable saltsthereof comprise: droxicam, enolicam, isoxicam, piroxicam, sudoxicam,tenoxicam and 4-hydroxyl-1,2-benzothiazine 1,1-dioxide4-(N-phenyl)-carboxamide. Structurally related oxicams having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

In still another specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or morepyrazoles, prodrug esters, or pharmaceutically acceptable salts thereof.The pyrazoles, prodrug esters, and pharmaceutically acceptable saltsthereof which may be used comprise: difenamizole and epirizole.Structurally related pyrazoles having similar analgesic andanti-inflammatory properties are also intended to be encompassed by thisgroup.

In an additional specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment or, concurrent treatment) with any of one or morepyrazolones, prodrug esters, or pharmaceutically acceptable saltsthereof. The pyrazolones, prodrug esters and pharmaceutically acceptablesalts thereof which may be used comprise: apazone, azapropazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propylphenazone, ramifenazone, suxibuzoneand thiazolinobutazone. Structurally related pyrazalones having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or more of thefollowing NSAIDs: ε-acetamidocaproic acid, S-adenosyl-methionine,3-amino-4-hydroxybutyric acid, amixetrine, anitrazafen, antrafenine,bendazac, bendazac lysinate, benzydamine, beprozin, broperamole,bucolome, bufezolac, ciproquazone, cloximate, dazidamine, deboxamet,detomidine, difenpiramide, difenpyramide, difisalamine, ditazol,emorfazone, fanetizole mesylate, fenflumizole, floctafenine, flumizole,flunixin, fluproquazone, fopirtoline, fosfosal, guaimesal, guaiazolene,isonixirn, lefetamine HCl, leflunomide, lofemizole, lotifazole, lysinclonixinate, meseclazone, nabumetone, nictindole, nimesulide, orgotein,orpanoxin, oxaceprol, oxapadol, paranyline, perisoxal, perisoxalcitrate, pifoxime, piproxen, pirazolac, pirfenidone, proquazone,proxazole, thielavin B, tiflamizole, timegadine, tolectin, tolpadol,tryptamid and those designated by company code number such as 480156S,AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C,CHINOIN 127, CN100, EB382, EL508, F1044, FK-506, GV3658, ITF182,KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102,PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281,SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706,U60257, UR2301 and WY41770. Structurally related NSAIDs having similaranalgesic and anti-inflammatory properties to the NSAIDs are alsointended to be encompassed by this group.

In still another specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment or concurrent treatment) with any of one or morecorticosteroids, prodrug esters or pharmaceutically acceptable saltsthereof for the treatment of the diseases and disorders recited herein,including acute and chronic inflammation such as rheumatic diseases,graft versus host disease and multiple sclerosis. Corticosteroids,prodrug esters and pharmaceutically acceptable salts thereof includehydrocortisone and compounds which are derived from hydrocortisone, suchas 21-acetoxypregnenolone, alclomerasone, algestone, amcinonide,beclomethasone, betamethasone, betamethasone valerate, budesonide,chloroprednisone, clobetasol, clobetasol propionate, clobetasone,clobetasone butyrate, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacon, desonide, desoximerasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flumethasone pivalate,flucinolone acetonide, flunisolide, fluocinonide, fluorocinoloneacetonide, fluocortin butyl, fluocortolone, fluocortolone hexanoate,diflucortolone valerate, fluorometholone, fluperolone acetate,fluprednidene acetate, fluprednisolone, flurandenolide, formocortal,halcinonide, halometasone, halopredone acetate, hydro-cortamate,hydrocortisone, hydrocortisone acetate, hydro-cortisone butyrate,hydrocortisone phosphate, hydrocortisone 21-sodium succinate,hydrocortisone tebutate, mazipredone, medrysone, meprednisone,methylprednisolone, mometasone furoate, paramethasone, prednicarbate,prednisolone, prednisolone 21-diedryaminoacetate, prednisolone sodiumphosphate, prednisolone sodium succinate, prednisolone sodium21-m-sulfobenzoate, prednisolone sodium 21-stearoglycolate, prednisolonetebutate, prednisolone 21-trimethylacetate, prednisone, prednival,prednylidene, prednylidene 21-diethylaminoacetate, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide andtriamcinolone hexacetonide. Structurally related corticosteroids havingsimilar analgesic and anti-inflammatory properties are also intended tobe encompassed by this group.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or moreslow-acting antirheumatic drugs (SAARDs) or disease modifyingantirheumatic drugs (DMARDS), prodrug esters, or pharmaceuticallyacceptable salts thereof for the treatment of the diseases and disordersrecited herein, including acute and chronic inflammation such asrheumatic diseases, graft versus host disease and multiple sclerosis.SAARDs or DMARDS, prodrug esters and pharmaceutically acceptable saltsthereof comprise: allocupreide sodium, auranofin, aurothioglucose,aurothioglycanide, azathioprine, brequinar sodium, bucillamine, calcium3-aurothio-2-propanol-1-sulfonate, chlorambucil, chloroquine,clobuzarit, cuproxoline, cyclo-phosphamide, cyclosporin, dapsone,15-deoxyspergualin, diacerein, glucosamine, gold salts (e.g., cycloquinegold salt, gold sodium thiomalate, gold sodium thiosulfate),hydroxychloroquine, hydroxychloroquine sulfate, hydroxyurea, kebuzone,levamisole, lobenzarit, melittin, 6-mercaptopurine, methotrexate,mizoribine, mycophenolate mofetil, myoral, nitrogen mustard,D-penicillamine, pyridinol imidazoles such as SKNF86002 and SB203580,rapamycin, thiols, thymopoietin and vincristine. Structurally relatedSAARDs or DMARDs having similar analgesic and anti-inflammatoryproperties are also intended to be encompassed by this group.

In another specific embodiment, the present invention is directed to theuse of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or more COX2inhibitors, prodrug esters or pharmaceutically acceptable salts thereoffor the treatment of the diseases and disorders recited herein,including acute and chronic inflammation. Examples of COX2 inhibitors,prodrug esters or pharmaceutically acceptable salts thereof include, forexample, celecoxib. Structurally related COX2 inhibitors having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group. Examples of COX-2 selective inhibitorsinclude but not limited to etoricoxib, valdecoxib, celecoxib,licofelone, lumiracoxib, rofecoxib, and the like.

In still another specific embodiment, the present invention is directedto the use of an antigen binding protein in combination (pretreatment,post-treatment, or concurrent treatment) with any of one or moreantimicrobials, prodrug esters or pharmaceutically acceptable saltsthereof for the treatment of the diseases and disorders recited herein,including acute and chronic inflammation. Antimicrobials include, forexample, the broad classes of penicillins, cephalosporins and otherbeta-lactams, aminoglycosides, azoles, quinolones, macrolides,rifamycins, tetracyclines, sulfonamides, lincosamides and polymyxins.The penicillins include, but are not limited to penicillin G, penicillinV, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin,floxacillin, ampicillin, ampicillin/sulbactam, amoxicillin,amoxicillin/clavulanate, hetacillin, cyclacillin, bacampicillin,carbenicillin, carbenicillin indanyl, ticarcillin,ticarcillin/clavulanate, aziocillin, mezlocillin, peperacillin, andmecillinam. The cephalosporins and other beta-lactams include, but arenot limited to cephalothin, cephapirin, cephalexin, cephradine,cefazolin, cefadroxil, cefaclor, cefamandole, cefotetan, cefoxitin,ceruroxime, cefonicid, ceforadine, cefixime, cefotaxime, moxalactam,ceftizoxime, cetriaxone, cephoperazone, ceftazidime, imipenem andaztreonam. The aminoglycosides include, but are not limited tostreptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycinand neomycin. The azoles include, but are not limited to fluconazole.The quinolones include, but are not limited to nalidixic acid,norfloxacin, enoxacin, ciprofloxacin, ofloxacin, sparfloxacin andtemafloxacin. The macrolides include, but are not limited toerythomycin, spiramycin and azithromycin. The rifamycins include, butare not limited to rifampin. The tetracyclines include, but are notlimited to spicycline, chlortetracycline, clomocycline, demeclocycline,deoxycycline, guamecycline, lymecycline, meclocycline, methacycline,minocycline, oxytetracycline, penimepicycline, pipacycline,rolitetracycline, sancycline, senociclin and tetracycline. Thesulfonamides include, but are not limited to sulfanilamide,sulfamethoxazole, sulfacetamide, sulfadiazine, sulfisoxazole andco-trimoxazole (trimethoprim/sulfamethoxazole). The lincosamidesinclude, but are not limited to clindamycin and lincomycin. Thepolymyxins (polypeptides) include, but are not limited to polymyxin Band colistin.

The most cited activity of IL-17A in vitro is the induction ofneutrophil mobilizing cytokines and chemokines by stromal cells (e.g.GM-CSF, IL6, IL8). These activities are potently enhanced in thepresence of TNF (Ruddy et al., 2004). Similarly the biologic activitiesof IL-17F are also enhanced by TNF co-stimulus. Of particular note withrespect to a pathogenic role for IL-17A in cartilage destruction andbone erosion associated with rheumatoid arthritis, IL-17A induces theexpression of NO, MMPs, PGE2 and RANKL and plays a role in antigenspecific T and B cell activation (Kolls and Linden, 2004, supra;Lubberts et al., 2005, Arthritis. Res. Ther. 7:29-37). Therefore, theantigen binding proteins may be used to inhibit the IL-17A and/orIL-17F/IL-17RA pathway and subsequent production of NO, MMPs, PGE2and/or RANKL and treat diseases associated with the IL-17A and/or IL-17Fupregulation of NO, MMPs, PGE2 and/or RANKL, as well as otherproinflammatory mediators described herein.

In addition to the presence of elevated levels of IL-17A in the synovialfluid of rheumatoid arthritis patients, several lines of evidencesuggest that IL-17A is a key pathogenic cytokine in arthritis. First,administration of IL-17A to the joints of mice exacerbates the symptomsof collagen-induced arthritis (Lubberts et al., 2003, J. Immunol.170:2655-2662). Second, soluble IL-17RA.Fc inhibits collagen breakdownin human RA synovial and bone explant cultures and attenuates thesymptoms in collagen induced arthritis in the mouse (Chabaud andMiossec, 2001, Arthritis Rheum. 44:1293-1303) (Lubberts et al., 2001, J.Immunol. 167:1004-1013)). As predicted from the low affinity interactionbetween IL-17F and IL-17R, IL-17R-Fc does not neutralize the activity ofIL-17F and so these effects are specific to IL-17A antagonism. Third,mice lacking IL-17A are resistant to IL-1-induced arthritis and havesuppressed collagen-induced arthritis (Nakae et al., 2003a, J. Immunol.171:6173-6177; Nakae et al., 2003b, supra). These data indicate thatIL-17A signaling through IL-17RA is an important mediator ofinflammation and joint damage in arthritis. The antigen binding proteinsmay be used to inhibit IL-17A and/or IL-17F/IL-17RA activity and therebyreduce the inflammation and joint damage in arthritis.

In rheumatoid arthritis, elevated levels of mature IL-17A have beendemonstrated in patient sera and synovial fluid. In some studies, IL-17Alevels were shown to correlate with disease activity and response todisease modifying treatment. Extremely elevated serum levels of IL-17Ahave consistently been measured in systemic Juvenile IdiopathicArthritis and the closely related Adult-Onset Still's Disease.WO2005/063290; Cannetti et al., 2003, J. Immunol. 171:1009-1015; Charleset al., 1999, J. Immunol. 163: 1521-1528; Cunnane et al., 2000, OnlineJ. Rheumatol. 27:58-63; Yoshimoto, 1998, J. Immunol. 161: 3400-3407. Theantigen binding proteins may be used to inhibit IL-17A and/orIL-17F/IL-17RA activity and thereby treat systemic Juvenile IdiopathicArthritis and Adult-Onset Still's Disease.

Various other autoimmune diseases have been associated with increasedlevels of IL-17A either in diseased tissue or in the serum. Theseinclude Systemic Lupus Erythematosus, atopic dermatitis, myastheniagravis, type I diabetes, and sarcoidosis. IL-17A may also be involved inasthma and GvHD. The antigen binding proteins taught herein may be usedto reduce the effects of the IL-17A and/or IL-17F/IL-17RA pathway inthese diseases.

The antigen binding proteins may be used to reduce IL-17RA activity,comprising administering an antigen binding protein. The presentinvention is also directed to methods of inhibiting binding and/orsignaling of IL-17A and/or IL-17F to IL-17RA comprising providing theantigen binding protein of the invention to IL-17RA. In certainembodiments, the antigen binding protein inhibits binding and/orsignaling of IL-17A and IL-17F to L-17RA. In additional embodiments, theantigen binding protein inhibits binding and/or signaling of IL-17A butnot IL-17F to IL-17RA. In other embodiments, the antigen binding proteininhibits binding and/or signaling of IL-17F and not L-17A to IL-17RA.The antigen binding proteins may be used in treating the consequences,symptoms, and/or the pathology associated with IL-17RA activity,comprising administering an antigen binding protein. The antigen bindingproteins may be used to inhibit the production of one or more of aninflammatory cytokine, chemokine, matrix metalloproteinase, or othermolecule associated with IL-17RA activation, comprising administering anantigen binding protein. The antigen binding proteins may be used inmethods of inhibiting production of molecules such as but is not limitedto: IL-6, IL-8, CXCL1, CXCL2, GM-CSF, G-CSF, M-CSF, IL-1β, TNFα, RANK-L,LIF, PGE2, IL-12, MMPs (such as but not limited to MMP3 and MMP9), GROα,NO, and/or C-telopeptide and the like, comprising administering anantigen binding protein. The antigen binding proteins inhibitproinflammatory and proautoimmune immune responses and may be used totreat diseases associated with activity of the IL-17A and/orIL-17F/IL-17RA pathway.

Aspects of the invention include antibodies that specifically bind tohuman IL-17RA and partially or fully inhibit IL-17RA from forming eithera homomeric or heteromeric functional receptor complex, such as, but notlimited to IL-17RA/IL-17RC complex and do not necessarily inhibit IL-17Aand/or IL-17F or an IL-17A/IL-17F heteromer from binding to IL-17RA or aIL-17RA heteromeric receptor complex. Thus, disease states associatedwith IL-17RC are also associated with IL-17RA due to the fact thatIL-17RC cannot signal without IL-17RA. For example, see You, Z., et al.,Cancer Res., 2006 Jan. 1; 66(1):175-83 and You, Z., et al., Neoplasia,2007 June; 9(6):464-70.

The IL-17RA antigen binding proteins may be used in methods of treatingIL-17RA associated disease, comprising administering an IL-17RA antigenbinding protein. The IL-17RA antigen binding protein may be used totreat diseases including, but are not limited to, inflammation,autoimmune disease, cartilage inflammation, and/or bone degradation,arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoidarthritis, pauciarticular juvenile rheumatoid arthritis, polyarticularjuvenile rheumatoid arthritis, systemic onset juvenile rheumatoidarthritis, juvenile ankylosing spondylitis, juvenile enteropathicarthritis, juvenile reactive arthritis, juvenile Reter's Syndrome, SEASyndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome), juveniledermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma,juvenile systemic lupus erythematosus, juvenile vasculitis,pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis,systemic onset rheumatoid arthritis, ankylosing spondylitis,enteropathic arthritis, reactive arthritis, Reter's Syndrome, SEASyndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome),dermatomyositis, psoriatic arthritis, scleroderma, systemic lupuserythematosus, vasculitis, myolitis, polymyolitis, dermatomyolitis,osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis,arteritis, ploymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis,primary biliary sclerosis, sclerosing cholangitis, Sjogren's syndrome,psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis,pustular psoriasis, erythrodermic psoriasis, dermatitis, atopicdermatitis, atherosclerosis, lupus, Still's disease, Systemic LupusErythematosus (SLE), myasthenia gravis, inflammatory bowel disease(IBD), Crohn's disease, ulcerative colitis, celiac disease, multiplesclerosis (MS), asthma, COPD, Guillain-Barre disease, Type I diabetesmellitus, Graves' disease, Addison's disease, Raynaud's phenomenon,autoimmune hepatitis, GVHD, and the like.

Chronic viral hepatitis affects over 500 million people worldwide,including approximately 10 million in the U.S. and Europe with chronichepatitis C infections. A significant proportion of chronic hepatitispatients develop progressive liver fibrosis and/or hepatocellularcarcinoma. While viral hepatitis vaccines are available or indevelopment, current therapy for infected individuals relies on longcourses of the combination of antiviral drugs and interferon-alpha(INF-α). INF-α is thought to be beneficial in treating viral hepatitisthrough its proven antiviral immunological activities andantiproliferative effects on fibroblasts, but the duration and level ofits use is limited by severe side effects.

Recent data describes how INF-α may be directly apoptotic for Th17 cells(American Association for Immunologists, abstract no. 42.8, May 12-16,2006, Boston). Th17 cells are a distinct subset of CD4+ T-cellsresponsible for producing IL-17A and IL-17F in response to IL-23(Harrington, et al., Nature Imm, 2005 vol. 6, no. 11, 1123-1132 andPark, et al., Nature Imm, 2005 vol. 6, no. 11, 1133-1141). We believethis suggests a new mechanism of action for INF-α in chronic viralhepatitis that does not involve direct action of INF-α on virus orfibroblasts, but indirect actions on Th17 cells. Furthermore, it hasrecently been discovered that Tumor Growth Factor-Beta (TGF-β) and/orIL-6, (see for example, Kimera, A., et al., PNAS U.S.A., 2007 Jul. 17;104(29):12099-104), both pro-fibrotic cytokine, also induces thedevelopment of TH17 cells by upregulating IL-23 receptor expression andthereby conferring responsiveness to IL-23 ((Mangan, et al., Nature,2006 vol. 441 no. 11, 231-234). Responsiveness to IL-23 induces thedifferentiation of naïve CD4+ T-cells into TH17 cells. As mentionedabove, the TH17 cells are responsible for releasing IL-17A and IL-17F,and IL-17A is known to have various stimulatory effects on fibroblastsin a number of tissues and organs. Taken together, we believe thatinhibition of the IL-17RA-IL-17A/IL-17F pathway may offer a therapeuticbenefit in the progressive fibrosis of chronic viral hepatitis.

An added benefit of inhibiting the IL-17RA-IL-17A/IL-17F pathway in thetreatment of viral hepatitis is that one may reduce the dosage of INF-αgiven to the patient and consequently limit the deleterious side effectsassociated with INF-α therapy. A further benefit of inhibiting theL-17RA-IL-17A/IL-17F pathway in the treatment of viral hepatitis is thepossibility of achieving a synergistic therapeutic effect with INF-αtherapy in combination with IL-17RA-IL-17A/IL-17F antagonist therapy, orother antagonists as described in more detail below.

Therefore, aspects of the invention are drawn to methods of treating thepathology associated with viral hepatitis by inhibiting the interactionbetween IL-17RA and IL-17A and/or IL-17F. Further aspects of theinvention are drawn to methods of inhibiting fibrosis by inhibiting theinteraction between IL-17RA and IL-17A and/or IL-17F. Further aspects ofthe invention are drawn to methods of treating fibrosis associated withviral hepatitis by inhibiting the interaction between IL-17RA and IL-17Aand/or IL-17F. Antagonists of the IL-17RA-IL-17A/IL-17F pathway may beused to inhibit the interaction between IL-17RA and IL-17A and/orIL-17F. Antagonists of the IL-17RA-IL-17A pathway include the IL-17RAantigen binding proteins described herein, as well as IL-17RA proteins(as well as biologically active fragments and fusion proteins thereof,such as IL-17RA-Fc fusion proteins), as well as antigen bindingproteins, such as antibodies and biologically active fragments thereof,that bind to IL-17A and inhibit IL-17A from activating IL-17RA, as wellas antigen binding proteins, such as antibodies and biologically activefragments thereof, that bind to IL-17F and inhibit IL-17F fromactivating IL-17RA.

Additional aspects are drawn to methods of treating the pathologyassociated with viral hepatitis by antagonizing the IL-23-IL-23 receptor(IL-23R) pathway. Further aspects of the invention are drawn to methodsof inhibiting fibrosis by antagonizing the IL-23-IL-23R pathway. Furtheraspects of the invention are drawn to methods of treating fibrosisassociated with viral hepatitis by antagonizing the IL-23-IL-23Rpathway. By antagonizing the IL-23-IL-23R pathway, one prevents theIL-23-induced differentiation of the TH17 cells and thereby ultimatelylimit the amount of circulating IL-17A and IL-17F, which may reduce thepathology associated with viral hepatitis. Antagonists to theIL-23-IL-23R pathway include antigen binding proteins, such asantibodies and biologically active fragments thereof, that bind to IL-23and block IL-23 from activating IL-23R. Additional antagonists toIL-23-IL-23R pathway include antigen binding proteins, such asantibodies and biologically active fragments thereof, that bind toIL-23R and block IL-23 from activating IL-23R. Additional antagonists toIL-23-IL-23R pathway include IL-23R proteins, as well as biologicallyactive fragments and fusion proteins thereof, such as IL-23R-Fc fusionproteins, that bind IL-23 and block IL-23 from activating IL-23R.

Additional aspects are drawn to methods of treating the pathologyassociated with viral hepatitis by antagonizing theTGF-β-TGF-βRI/TGF-βRII pathway. Further aspects of the invention aredrawn to methods of inhibiting fibrosis by antagonizing theTGF-β-TGF-βRI/TGF-βRII pathway. Further aspects of the invention aredrawn to methods of treating fibrosis associated with viral hepatitis byantagonizing the TGF-β-TGF-βRI/TGF-βRII pathway. By antagonizing theTGF-β-TGF-βRI/TGF-βRII pathway, one prevents the TGF-β-induceddevelopment of the TH17 cells and thereby ultimately limit the amount ofcirculating IL-17A and IL-17F, which may reduce the pathology associatedwith viral hepatitis. Antagonists to the TGF-β-TGF-βRI/TGF-βRII pathwayinclude antigen binding proteins, such as antibodies and biologicallyactive fragments thereof, that bind to TGF-β and block TGF-β fromactivating TGF-βRI and/or TGF-βRII. Additional antagonists to theTGF-β-TGF-βRI/TGF-βRII pathway include antigen binding proteins, such asantibodies and biologically active fragments thereof, that bind toTGF-βRI or TGF-βRII and block TGF-β from activating TGF-βRI or TGF-βRII.

Additional aspects are drawn to methods of treating the pathologyassociated with viral hepatitis by antagonizing the IL-6-IL-6R pathway.Further aspects of the invention are drawn to methods of inhibitingfibrosis by antagonizing the IL-6-IL-6R pathway. Further aspects of theinvention are drawn to methods of treating fibrosis associated withviral hepatitis by antagonizing the IL-6-IL-6R pathway. By antagonizingthe IL-6-IL-6R pathway, one may reduce the pathology associated withviral hepatitis. Antagonists to the IL-6-IL-6R pathway include antigenbinding proteins, such as antibodies and biologically active fragmentsthereof, that bind to IL-6 and block IL-6 from activating IL-6R.Additional antagonists to the IL-6-IL-6R pathway include antigen bindingproteins, such as antibodies and biologically active fragments thereof,that bind to IL-6R and block IL-6 from activating IL-6R.

Further aspects include combination therapy using the antagonists of theIL-17RA-IL-17A/IL-17F pathway, IL-23-IL-23R pathway,TGF-β-TGF-βRI/TGF-βRII pathway, and/or the IL-6-IL-6R pathway mentionedabove in combination with each other, as well as in combination withart-recognized hepatitis therapies, such as but not limited to,interferon, and in particular INF-α. All permutations of thesecombinations are envisioned.

Further aspects include combination therapy using the antagonists of theIL-17RA-IL-17A/IL-17F pathway, IL-23-IL-23R pathway,TGF-β-TGF-βRI/TGF-βRII pathway, and/or the IL-6-IL-6R pathway mentionedabove in combination with each other, as well as in combination withart-recognized hepatitis therapies, such as but not limited to,interferon, and in particular INF-α, as well as with antiviral agents,such as but not limited to Adefovir dipivoxil, acyclic analogues ofdeoxyadenosine monophosphate (Adefovir, Tenofovir disoproxil fumarate),(−) enantiomer of the deoxycytidine analogue 2′-deoxy-3′-thiacytidine(Lamivudine), carbocyclic deoxyguanosine analogues (Entecavir),L-nucleosides (β-L-2′-Deoxythymidine, β-L-2′-deoxycytidine, andβ-L-2′-deoxyadenosine), [(−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine](Emtricitabine), 1-β-2,6-Diaminopurine dioxalane (DAPD, amdoxovir),2′-Fluoro-5-methyl-β-L-arabinofuranosyluridine (L-FMAU, clevudine),Famciclovir, and/or Penciclovir. All permutations of these combinationsare envisioned.

Diagnostic Methods

The antigen binding proteins of the invention can be used for diagnosticpurposes to detect, diagnose, or monitor diseases and/or conditionsassociated with IL-17A or IL-17RA. The invention provides for thedetection of the presence of IL-17RA in a sample using classicalimmunohistological methods known to those of skill in the art (e.g.,Tijssen, 1993, Practice and Theory of Enzyme Immunoassays, vol 15 (EdsR. H. Burdon and P. H. van Knippenberg, Elsevier, Amsterdam); Zola,1987, Monoclonal Antibodies: A Manual of Techniques, pp. 147-158 (CRCPress, Inc.); Jalkanen et al., 1985, J. Cell. Biol. 101:976-985;Jalkanen et al., 1987, J. Cell Biol. 105:3087-3096). The detection ofIL-17RA can be performed in vivo or in vitro.

Diagnostic applications provided herein include use of the antigenbinding proteins to detect expression of IL-17RA and binding of theligands to IL-17RA. Examples of methods useful in the detection of thepresence of IL-17RA include immunoassays, such as the enzyme linkedimmunosorbent assay (ELISA) and the radioimmunoassay (RIA).

For diagnostic applications, the antigen binding protein typically willbe labeled with a detectable labeling group. Suitable labeling groupsinclude, but are not limited to, the following: radioisotopes orradionuclides (e.g., ³H, ¹⁴C, ¹⁵N, ³⁵S, ⁹⁰Y, ⁹⁹Tc, ¹¹¹In, ¹²⁵I, ¹³¹I),fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors),enzymatic groups (e.g., horseradish peroxidase, β-galactosidase,luciferase, alkaline phosphatase), chemiluminescent groups, biotinylgroups, or predetermined polypeptide epitopes recognized by a secondaryreporter (e.g., leucine zipper pair sequences, binding sites forsecondary antibodies, metal binding domains, epitope tags). In someembodiments, the labelling group is coupled to the antigen bindingprotein via spacer arms of various lengths to reduce potential sterichindrance. Various methods for labelling proteins are known in the artand may be used in performing the present invention.

One aspect of the invention provides for identifying a cell or cellsthat express IL-17RA. In a specific embodiment, the antigen bindingprotein is labeled with a labeling group and the binding of the labeledantigen binding protein to IL-17RA is detected. In a further specificembodiment, the binding of the antigen binding protein to IL-17RAdetected in vivo. In a further specific embodiment, the antigen bindingprotein-IL-17RA is isolated and measured using techniques known in theart. See, for example, Harlow and Lane, 1988, Antibodies: A LaboratoryManual, New York: Cold Spring Harbor (ed. 1991 and periodicsupplements); John E. Coligan, ed., 1993, Current Protocols InImmunology New York: John Wiley & Sons.

Another aspect of the invention provides for detecting the presence of atest molecule that competes for binding to IL-17RA with the antigenbinding proteins of the invention. An example of one such assay wouldinvolve detecting the amount of free antigen binding protein in asolution containing an amount of IL-17RA in the presence or absence ofthe test molecule. An increase in the amount of free antigen bindingprotein (i.e., the antigen binding protein not bound to IL-17RA) wouldindicate that the test molecule is capable of competing for IL-17RAbinding with the antigen binding protein. In one embodiment, the antigenbinding protein is labeled with a labeling group. Alternatively, thetest molecule is labeled and the amount of free test molecule ismonitored in the presence and absence of an antigen binding protein.

Aspects of the invention include the use of the IL-17RA antigen bindingproteins in in vitro assays for research purposes, such as to inhibitproduction of molecules such as but is not limited to: IL-6, IL-8,CXCL1, CXCL2, GM-CSF, G-CSF, M-CSF, IL-1β, TNFα, RANK-L, LIF, PGE2,IL-12, MMPs (such as but not limited to MMP3 and MMP9), GROα, NO, and/orC-telopeptide and the like. Antibodies directed against an IL-17RA canbe used, for example, in purifying IL-17RA proteins by immunoaffinitychromatography.

Methods of Treatment: Pharmaceutical Formulations, Routes ofAdministration

In some embodiments, the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of one or a plurality ofthe antigen binding proteins of the invention together with apharmaceutically acceptable diluent, carrier, solubilizer, emulsifier,preservative, and/or adjuvant. In addition, the invention providesmethods of treating a patient by administering such pharmaceuticalcomposition. The term “patient” includes human and animal subjects.

Pharmaceutical compositions comprising one or more antigen bindingproteins may be used to reduce IL-17RA activity. Pharmaceuticalcompositions comprising one or more antigen binding proteins may be usedin treating the consequences, symptoms, and/or the pathology associatedwith IL-17RA activity. Pharmaceutical compositions comprising one ormore antigen binding proteins may be used in methods of inhibitingbinding and/or signaling of IL-17A and/or IL-17F to IL-17RA comprisingproviding the antigen binding protein of the invention to IL-17RA. Incertain embodiments, the antigen binding protein inhibits binding and/orsignaling of IL-17A and IL-17F to IL-17RA. In additional embodiments,pharmaceutical compositions comprising one or more antigen bindingproteins may be used in methods of inhibiting binding and/or signalingof IL-17A but not IL-17F to IL-17RA. In other embodiments,pharmaceutical compositions comprising one or more antigen bindingproteins may be used in methods of inhibiting binding and/or signalingof IL-17F and not IL-17A to IL-17RA. Aspects of the invention includeantibodies that specifically bind to human IL-17RA and inhibit IL-17Aand/or IL-17F from binding and activating IL-17RA, or a heteromericcomplex of IL-17RA and IL-17RC. Aspects of the invention includeantibodies that specifically bind to human IL-17RA and inhibit anIL-17A/IL-17F heteromer from binding and activating IL-17RA, or aheteromeric complex of IL-17RA and IL-17RC. Throughout thespecification, when reference is made to inhibiting IL-17A and/orIL-17F, it is understood that this also includes inhibiting heteromersof IL-17A and IL-17F. Aspects of the invention include antibodies thatspecifically bind to human IL-17RA and partially or fully inhibitIL-17RA from forming either a homomeric or heteromeric functionalreceptor complex, such as, but not limited to IL-17RA-IL-17RC complex.Aspects of the invention include antibodies that specifically bind tohuman IL-17RA and partially or fully inhibit IL-17RA from forming eithera homomeric or heteromeric functional receptor complex, such as, but notlimited to IL-17RA/IL-17RC complex and do not necessarily inhibit IL-17Aand/or IL-17F or an IL-17A/IL-17F heteromer from binding to IL-17RA or aIL-17RA heteromeric receptor complex.

Pharmaceutical compositions comprising one or more antigen bindingproteins may be used in methods of treating the consequences, symptoms,and/or the pathology associated with IL-17RA activity. Pharmaceuticalcompositions comprising one or more antigen binding proteins may be usedin methods of inhibiting the production of one or more of aninflammatory cytokine, chemokine, matrix metalloproteinase, or othermolecule associated with IL-17RA activation, comprising administering anIL-17RA antigen binding protein. Pharmaceutical compositions comprisingone or more antigen binding proteins may be used in methods ofinhibiting production of IL-6, IL-8, GM-CSF, NO, MMPs, PGE2 RANKL,and/or C-telopeptide, and the like.

Pharmaceutical compositions comprising one or more antigen bindingproteins may be used to treat diseases and conditions including, but arenot limited to, inflammation, autoimmune disease, cartilageinflammation, and/or bone degradation, arthritis, rheumatoid arthritis,juvenile arthritis, juvenile rheumatoid arthritis, pauciarticularjuvenile rheumatoid arthritis, polyarticular juvenile rheumatoidarthritis, systemic onset juvenile rheumatoid arthritis, juvenileankylosing spondylitis, juvenile enteropathic arthritis, juvenilereactive arthritis, juvenile Reter's Syndrome, SEA Syndrome(Seronegativity, Enthesopathy, Arthropathy Syndrome), juveniledermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma,juvenile systemic lupus erythematosus, juvenile vasculitis,pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis,systemic onset rheumatoid arthritis, ankylosing spondylitis,enteropathic arthritis, reactive arthritis, Reter's Syndrome, SEASyndrome (Seronegativity, Enthesopathy, Arthropathy Syndrome),dermatomyositis, psoriatic arthritis, scleroderma, systemic lupuserythematosus, vasculitis, myolitis, polymyolitis, dermatomyolitis,osteoarthritis, polyarteritis nodossa, Wegener's granulomatosis,arteritis, ploymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis,primary biliary sclerosis, sclerosing cholangitis, Sjogren's syndrome,psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis,pustular psoriasis, erythrodermic psoriasis, dermatitis, atopicdermatitis, atherosclerosis, lupus, Still's disease, Systemic LupusErythematosus (SLE), myasthenia gravis, inflammatory bowel disease(IBD), Crohn's disease, ulcerative colitis, celiac disease, multiplesclerosis (MS), asthma, COPD, Guillain-Barre disease, Type I diabetesmellitus, Graves' disease, Addison's disease, Raynaud's phenomenon,autoimmune hepatitis, GVHD, and the like.

Preferably, acceptable formulation materials are nontoxic to recipientsat the dosages and concentrations employed. In specific embodiments,pharmaceutical compositions comprising a therapeutically effectiveamount of IL-17RA antigen binding proteins are provided.

In certain embodiments, acceptable formulation materials preferably arenontoxic to recipients at the dosages and concentrations employed. Incertain embodiments, the pharmaceutical composition may containformulation materials for modifying, maintaining or preserving, forexample, the pH, osmolarity, viscosity, clarity, color, isotonicity,odor, sterility, stability, rate of dissolution or release, adsorptionor penetration of the composition. In such embodiments, suitableformulation materials include, but are not limited to, amino acids (suchas glycine, glutamine, asparagine, arginine or lysine); antimicrobials;antioxidants (such as ascorbic acid, sodium sulfite or sodiumhydrogen-sulfite); buffers (such as borate, bicarbonate, Tris-HCl,citrates, phosphates or other organic acids); bulking agents (such asmannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine,polyvinylpyrrolidone, beta-cyclodextrin orhydroxypropyl-beta-cyclodextrin); fillers; monosaccharides;disaccharides; and other carbohydrates (such as glucose, mannose ordextrins); proteins (such as serum albumin, gelatin or immunoglobulins);coloring, flavoring and diluting agents; emulsifying agents; hydrophilicpolymers (such as polyvinylpyrrolidone); low molecular weightpolypeptides; salt-forming counterions (such as sodium); preservatives(such as benzalkonium chloride, benzoic acid, salicylic acid,thimerosal, phenethyl alcohol, methylparaben, propylparaben,chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such asglycerin, propylene glycol or polyethylene glycol); sugar alcohols (suchas mannitol or sorbitol); suspending agents; surfactants or wettingagents (such as pluronics, PEG, sorbitan esters, polysorbates such aspolysorbate 20, polysorbate, triton, tromethamine, lecithin,cholesterol, tyloxapal); stability enhancing agents (such as sucrose orsorbitol); tonicity enhancing agents (such as alkali metal halides,preferably sodium or potassium chloride, mannitol sorbitol); deliveryvehicles; diluents; excipients and/or pharmaceutical adjuvants. See,REMINGTON'S PHARMACEUTICAL SCIENCES, 18″ Edition, (A. R. Genrmo, ed.),1990, Mack Publishing Company.

In certain embodiments, the optimal pharmaceutical composition will bedetermined by one skilled in the art depending upon, for example, theintended route of administration, delivery format and desired dosage.See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, supra. In certainembodiments, such compositions may influence the physical state,stability, rate of in vivo release and rate of in vivo clearance of theantigen binding proteins of the invention. In certain embodiments, theprimary vehicle or carrier in a pharmaceutical composition may be eitheraqueous or non-aqueous in nature. For example, a suitable vehicle orcarrier may be water for injection, physiological saline solution orartificial cerebrospinal fluid, possibly supplemented with othermaterials common in compositions for parenteral administration. Neutralbuffered saline or saline mixed with serum albumin are further exemplaryvehicles. In specific embodiments, pharmaceutical compositions compriseTris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5,and may further include sorbitol or a suitable substitute therefor. Incertain embodiments of the invention, IL-17RA antigen binding proteincompositions may be prepared for storage by mixing the selectedcomposition having the desired degree of purity with optionalformulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES, supra) in theform of a lyophilized cake or an aqueous solution. Further, in certainembodiments, the IL-17RA antigen binding protein product may beformulated as a lyophilizate using appropriate excipients such assucrose.

The pharmaceutical compositions of the invention can be selected forparenteral delivery. Alternatively, the compositions may be selected forinhalation or for delivery through the digestive tract, such as orally.Preparation of such pharmaceutically acceptable compositions is withinthe skill of the art. The formulation components are present preferablyin concentrations that are acceptable to the site of administration. Incertain embodiments, buffers are used to maintain the composition atphysiological pH or at a slightly lower pH, typically within a pH rangeof from about 5 to about 8.

When parenteral administration is contemplated, the therapeuticcompositions for use in this invention may be provided in the form of apyrogen-free, parenterally acceptable aqueous solution comprising thedesired IL-17RA antigen binding protein in a pharmaceutically acceptablevehicle. A particularly suitable vehicle for parenteral injection issterile distilled water in which the IL-17RA antigen binding protein isformulated as a sterile, isotonic solution, properly preserved. Incertain embodiments, the preparation can involve the formulation of thedesired molecule with an agent, such as injectable microspheres,bio-erodible particles, polymeric compounds (such as polylactic acid orpolyglycolic acid), beads or liposomes, that may provide controlled orsustained release of the product which can be delivered via depotinjection. In certain embodiments, hyaluronic acid may also be used,having the effect of promoting sustained duration in the circulation. Incertain embodiments, implantable drug delivery devices may be used tointroduce the desired antigen binding protein.

Pharmaceutical compositions of the invention can be formulated forinhalation. In these embodiments, IL-17RA antigen binding proteins areadvantageously formulated as a dry, inhalable powder. In specificembodiments, IL-17RA antigen binding protein inhalation solutions mayalso be formulated with a propellant for aerosol delivery. In certainembodiments, solutions may be nebulized. Pulmonary administration andformulation methods therefore are further described in InternationalPatent Application No. PCT/US94/001875, which is incorporated byreference and describes pulmonary delivery of chemically modifiedproteins. It is also contemplated that formulations can be administeredorally. IL-17RA antigen binding proteins that are administered in thisfashion can be formulated with or without carriers customarily used inthe compounding of solid dosage forms such as tablets and capsules. Incertain embodiments, a capsule may be designed to release the activeportion of the formulation at the point in the gastrointestinal tractwhen bioavailability is maximized and pre-systemic degradation isminimized. Additional agents can be included to facilitate absorption ofthe IL-17RA antigen binding protein. Diluents, flavorings, low meltingpoint waxes, vegetable oils, lubricants, suspending agents, tabletdisintegrating agents, and binders may also be employed.

A pharmaceutical composition of the invention is preferably provided tocomprise an effective quantity of one or a plurality of IL-17RA antigenbinding proteins in a mixture with non-toxic excipients that aresuitable for the manufacture of tablets. By dissolving the tablets insterile water, or another appropriate vehicle, solutions may be preparedin unit-dose form. Suitable excipients include, but are not limited to,inert diluents, such as calcium carbonate, sodium carbonate orbicarbonate, lactose, or calcium phosphate; or binding agents, such asstarch, gelatin, or acacia; or lubricating agents such as magnesiumstearate, stearic acid, or talc.

Additional pharmaceutical compositions will be evident to those skilledin the art, including formulations involving IL-17RA antigen bindingproteins in sustained- or controlled-delivery formulations. Techniquesfor formulating a variety of other sustained- or controlled-deliverymeans, such as liposome carriers, bio-erodible microparticles or porousbeads and depot injections, are also known to those skilled in the art.See, for example, International Patent Application No. PCT/US93/00829,which is incorporated by reference and describes controlled release ofporous polymeric microparticles for delivery of pharmaceuticalcompositions. Sustained-release preparations may include semipermeablepolymer matrices in the form of shaped articles, e.g., films, ormicrocapsules. Sustained release matrices may include polyesters,hydrogels, polylactides (as disclosed in U.S. Pat. No. 3,773,919 andEuropean Patent Application Publication No. EP 058481, each of which isincorporated by reference), copolymers of L-glutamic acid and gammaethyl-L-glutamate (Sidman et al., 1983, Biopolymers 2:547-556), poly(2-hydroxyethyl-methacrylate) (Langer et al., 1981, J. Biomed. Mater.Res. 15:167-277 and Langer, 1982, Chem. Tech. 12:98-105), ethylene vinylacetate (Langer et al., 1981, supra) or poly-D(−)-3-hydroxybutyric acid(European Patent Application Publication No. EP 133,988). Sustainedrelease compositions may also include liposomes that can be prepared byany of several methods known in the art. See, e.g., Eppstein et al.,1985, Proc. Natl. Acad. Sci. U.S.A. 82:3688-3692; European PatentApplication Publication Nos. EP 036,676; EP 088,046 and EP 143,949,incorporated by reference.

Pharmaceutical compositions used for in vivo administration aretypically provided as sterile preparations. Sterilization can beaccomplished by filtration through sterile filtration membranes. Whenthe composition is lyophilized, sterilization using this method may beconducted either prior to or following lyophilization andreconstitution. Compositions for parenteral administration can be storedin lyophilized form or in a solution. Parenteral compositions generallyare placed into a container having a sterile access port, for example,an intravenous solution bag or vial having a stopper pierceable by ahypodermic injection needle.

Aspects of the invention includes self-buffering IL-17RA antigen bindingprotein formulations, which can be used as pharmaceutical compositions,as described in international patent application WO 06138181A2(PCT/US2006/022599), which is incorporated by reference in its entiretyherein. One embodiment provides self-buffering IL-17RA antigen bindingprotein formulations comprising an IL-17RA antigen binding protein inwhich the total salt concentration is less than 150 mM.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations that further comprise an IL-17RA antigen binding proteinand one or more polyols and/or one or more surfactants. One embodimentprovides self-buffering IL-17RA antigen binding protein formulationscomprising an IL-17RA antigen binding protein, in which the total saltconcentration is less than 150 mM, that further comprise one or moreexcipients, including but not limited to, pharmaceutically acceptablesalts; osmotic balancing agents (tonicity agents); surfactants, polyols,anti-oxidants; antibiotics; antimycotics; bulking agents;lyoprotectants; anti-foaming agents; chelating agents; preservatives;colorants; and analgesics. One embodiment provides self-bufferingIL-17RA antigen binding protein formulations comprising an IL-17RAantigen binding protein and one or more other pharmaceutically activeagents.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein, wherein theIL-17RA antigen binding protein has a buffer capacity per unit volumeper pH unit of at least that of approximately: 2.0 or 3.0 or 4.0 or 5.0or 6.50 or 8.00 or 10.0 or 15.0 or 20.0 or 30.0 or 40.0 or 50.0 or 75.0or 100 or 125 or 150 or 200 or 250 or 300 or 350 or 400 or 500 or 700 or1,000 or 1,500 or 2,000 or 2,500 or 3,000 or 4,000 or 5,000 mM sodiumacetate buffer in pure water over the range of pH 5.0 to 4.0 or pH 5.0to 5.5, or at least 2.0 mM, or at least 3.0 mM, or at least 4.0 mM or atleast 5.0 mM, or at least 7.5 mM, or at least 10 mM, or at least 20 mM.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations wherein, exclusive of the buffer capacity of the protein,the buffer capacity per unit volume per pH unit of the formulation isequal to or less than that of 1.0 or 1.5 or 2.0 or 3.0 or 4.0 or 5.0 mMsodium acetate buffer in pure water over the range of pH 4.0 to 5.0 orpH 5.0 to 5.5, or optionally less than that of 1.0 mM, optionally lessthan that of 2.0 mM, optionally less than that of 2.5 mM, optionallyless than that of 3.0 mM, and optionally less than that of 5.0 mM.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein overthe range of plus or minus 1 pH unit from the pH of the formulation, thebuffer capacity of the IL-17RA antigen binding protein is at leastapproximately: 1.00 or 1.50 or 1.63 or 2.00 or 3.00 or 4.00 or 5.00 or6.50 or 8.00 or 10.0 or 15.0 or 20.0 or 30.0 or 40.0 or 50.0 or 75.0 or100 or 125 or 150 or 200 or 250 or 300 or 350 or 400 or 500 or 700 or1,000 or 1,500 or 2,000 or 2,500 or 3,000 or 4,000 or 5,000 mEq perliter per pH unit, optionally at least approximately 1.00, optionally atleast approximately 1.50, optionally at least approximately 1.63,optionally at least approximately 2.00, optionally at leastapproximately 3.00, optionally at least approximately 5.0, optionally atleast approximately 10.0, and optionally at least approximately 20.0.One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein overthe range of plus or minus 1 pH unit from the pH of the formulation,exclusive of the IL-17RA antigen binding protein, the buffer capacityper unit volume per pH unit of the formulation is equal to or less thanthat of 0.50 or 1.00 or 1.50 or 2.00 or 3.00 or 4.00 or 5.00 or 6.50 or8.00 or 10.0 or 20.0 or 25.0 mM sodium acetate buffer in pure water overthe range pH 5.0 to 4.0 or pH 5.0 to 5.5.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein overa range of plus or minus 1 pH unit from a desired pH, the proteinprovides at least approximately 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 97%, 98%, 99%, or 99.5% of the buffer capacity of the formulation,optionally at least approximately 75%, optionally at least approximately85%, optionally at least approximately 90%, optionally at leastapproximately 95%, optionally at least approximately 99% of the buffercapacity of the formulation.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein theconcentration of the IL-17RA antigen binding protein is betweenapproximately: 20 and 400, or 20 and 300, or 20 and 250, or 20 and 200,or 20 and 150 mg/ml, optionally between approximately 20 and 400 mg/ml,optionally between approximately 20 and 250, and optionally betweenapproximately 20 and 150 mg/ml.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein thepH maintained by the buffering action of the IL-17RA antigen bindingprotein is between approximately: 3.5 and 8.0, or 4.0 and 6.0, or 4.0and 5.5, or 4.0 and 5.0, optionally between approximately 3.5 and 8.0,and optionally between approximately 4.0 and 5.5.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein thesalt concentration is less than: 150 mM or 125 mM or 100 mM or 75 mM or50 mM or 25 mM, optionally 150 mM, optionally 125 mM, optionally 100 mM,optionally 75 mM, optionally 50 mM, and optionally 25 mM.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein and one ormore pharmaceutically acceptable salts; polyols; surfactants; osmoticbalancing agents; tonicity agents; anti-oxidants; antibiotics;antimycotics; bulking agents; lyoprotectants; anti-foaming agents;chelating agents; preservatives; colorants; analgesics; or additionalpharmaceutical agents.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein and one ormore pharmaceutically acceptable polyols in an amount that is hypotonic,isotonic, or hypertonic, preferably approximately isotonic, particularlypreferably isotonic, such as but not limited to any one or more ofsorbitol, mannitol, sucrose, trehalose, or glycerol, optionallyapproximately 5% sorbitol, 5% mannitol, 9% sucrose, 9% trehalose, or2.5% glycerol.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein furthercomprising a surfactant, preferably one or more of polysorbate 20,polysorbate 80, other fatty acid esters of sorbitan, polyethoxylates,and poloxamer 188, preferably polysorbate 20 or polysorbate 80,optionally approximately 0.001 to 0.1% polysorbate 20 or polysorbate 80,optionally approximately 0.002 to 0.02% polysorbate 20 or polysorbate80, or optionally 0.002 to 0.02% polysorbate 20 or polysorbate 80.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein wherein theformulation is sterile and suitable for treatment of a human ornon-human subject.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein and asolvent, the IL-17RA antigen binding protein having a buffer capacityper unit volume per pH unit of at least that of 4.0 mM sodium acetate inwater over the range of pH 4.0 to 5.0 or pH 5.0 to 5.5, wherein thebuffer capacity per unit volume of the formulation exclusive of theIL-17RA antigen binding protein is equal to or less than that of 2.0 mMsodium acetate in water over the same ranges preferably determined inthe same way.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein and asolvent, wherein at the pH of the formulation the buffer capacity of theprotein is at least 1.63 mEq per liter for a pH change of theformulation of plus or minus 1 pH unit wherein the buffer capacity ofthe formulation exclusive of the protein is equal to or less than 0.81mEq per liter at the pH of the formulation for a pH change of plus orminus 1 pH unit.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations comprising an IL-17RA antigen binding protein, wherein theformulation is in the form of a lyophilate which upon reconstitutionprovides a formulation in accordance with any of the foregoing orfollowing.

One embodiment provides self-buffering IL-17RA antigen binding proteinformulations in a kit comprising one or more vials containing aself-buffering IL-17RA antigen binding protein formulation or alyophilate of a self-buffering IL-17RA antigen binding proteinformulation in accordance with any of the foregoing or the following,and instructions regarding use thereof.

One embodiment provides a process for preparing a self-buffering IL-17RAantigen binding protein formulation or a lyophilate thereof according toany of the foregoing or the following, comprising removing residualbuffer using a counter ion.

One embodiment provides a process for preparing a self-buffering IL-17RAantigen binding protein formulation or a lyophilate thereof according toany of the foregoing or the following, comprising removing residualbuffer using any one or more of the following in the presence of acounter ion: chromatography, dialysis, and/or tangential flowfiltration.

One embodiment provides a process for preparing a self-buffering IL-17RAantigen binding protein formulation or a lyophilate thereof according toany of the foregoing or the following, comprising removing residualbuffer using tangential flow filtration.

One embodiment provides a process for preparing a self-buffering IL-17RAantigen binding protein formulation or a lyophilate thereof according toany of the foregoing or the following comprising a step of dialysisagainst a solution at a pH below that of the preparation, and, ifnecessary, adjusting the pH thereafter by addition of dilute acid ordilute base.

As discussed above, certain embodiments provide self-buffering IL-17RAantigen binding proteins protein compositions, particularlypharmaceutical IL-17RA antigen binding protein compositions, thatcomprise, in addition to the IL-17RA antigen binding protein, one ormore excipients such as those illustratively described in this sectionand elsewhere herein. Excipients can be used in the invention in thisregard for a wide variety of purposes, such as adjusting physical,chemical, or biological properties of formulations, such as adjustmentof viscosity, and or processes of the invention to improve effectivenessand or to stabilize such formulations and processes against degradationand spoilage due to, for instance, stresses that occur duringmanufacturing, shipping, storage, pre-use preparation, administration,and thereafter.

A variety of expositions are available on protein stabilization andformulation materials and methods useful in this regard, such as Arakawaet al., “Solvent interactions in pharmaceutical formulations,” PharmRes. 8(3): 285-91 (1991); Kendrick et al., “Physical stabilization ofproteins in aqueous solution,” in: RATIONAL DESIGN OF STABLE PROTEINFORMULATIONS: THEORY AND PRACTICE, Carpenter and Manning, eds.Pharmaceutical Biotechnology. 13: 61-84 (2002), and Randolph et al.,“Surfactant-protein interactions,” Pharm Biotechnol. 13: 159-75 (2002),each of which is herein incorporated by reference in its entirety,particularly in parts pertinent to excipients and processes of the samefor self-buffering protein formulations in accordance with the currentinvention, especially as to protein pharmaceutical products andprocesses for veterinary and/or human medical uses.

Various excipients useful in the invention are listed in TABLE 3 andfurther described below.

TABLE 3 Types of Excipients and Their Functions Function Type LiquidsLyophilates Tonicity Provides isotonicity to the formulation such thatStabilizers include cryo and lyoprotectants Agents/ it is suitable forinjection Examples include polyols, sugars and polymers StabilizersExamples include polyols, salts, and amino acids Cryoprotectants protectproteins from freezing Help maintain the protein in a more compactstresses state (polyols) Lyoprotectants stabilize proteins in thefreeze- Minimize electrostatic, solution protein-protein dried stateinteractions (salts) Bulking Not applicable Used to enhance productelegance and to prevent Agents blowout Provides structural strength tothe lyo cake Examples include mannitol and glycine SurfactantsPrevent/control aggregation, particle formation Employed if aggregationduring the and surface adsorption of drug lyophilization process is anissue Examples include polysorbate 20 and 80 May serve to reducereconstitution times Examples include polysorbate 20 and 80Anti-oxidants Control protein oxidation Usually not employed, molecularreactions in the lyophilized cake are greatly retarded Metal A specificmetal ion is included in a liquid May be included if a specific metalion is Ions/ formulation only as a co-factor included only as aco-factor Chelating Divalent cations such as zinc and magnesium areChelating agents are generally not needed in Agents utilized insuspension formulations lyophilized formulations Chelating agents areused to inhibit heavy metal ion catalyzed reactions PreservativesImportant particularly for multi-dose For multi-dose formulations onlyformulations Provides protection against microbial growth in Protectsagainst microbial growth, formulation Example: benzyl alcohol Is usuallyincluded in the reconstitution diluent (e.g. bWFI)

Salts may be used in accordance with certain embodiments of theinvention to, for example, adjust the ionic strength and/or theisotonicity of a self-buffering formulation and/or to improve thesolubility and/or physical stability of a self-buffering protein orother ingredient of a self-buffering protein composition in accordancewith the invention.

As is well known, ions can stabilize the native state of proteins bybinding to charged residues on the protein's surface and by shieldingcharged and polar groups in the protein and reducing the strength oftheir electrostatic interactions, attractive, and repulsiveinteractions. Ions also can stabilize the denatured state of a proteinby binding to, in particular, the denatured peptide linkages (—CONH) ofthe protein. Furthermore, ionic interaction with charged and polargroups in a protein also can reduce intermolecular electrostaticinteractions and, thereby, prevent or reduce protein aggregation andinsolubility.

Ionic species differ significantly in their effects on proteins. Anumber of categorical rankings of ions and their effects on proteinshave been developed that can be used in formulating self-bufferingprotein compositions in accordance with the invention. One example isthe Hofmeister series, which ranks ionic and polar non-ionic solutes bytheir effect on the conformational stability of proteins in solution.Stabilizing solutes are referred to as “kosmotropic.” Destabilizingsolutes are referred to as chaotropic. Kosmotropes commonly are used athigh concentrations (e.g., >1 molar ammonium sulfate) to precipitateproteins from solution (“salting-out”). Chaotropes commonly are used todenture and/or to solubilize proteins (“salting-in”). The relativeeffectiveness of ions to “salt-in” and “salt-out” defines their positionin the Hofmeister series.

In addition to their utilities and their drawbacks (as discussed above)salts also are effective for reducing the viscosity of proteinformulations and can be used in the invention for that purpose. In orderto maintain isotonicity in a parenteral formulation in accordance withpreferred embodiments of the invention, improve protein solubilityand/or stability, improve viscosity characteristics, avoid deleterioussalt effects on protein stability and aggregation, and preventsalt-mediated protein degradation, the salt concentration inself-buffering formulations in accordance with various preferredembodiments of the invention are less than 150 mM (as to monovalentions) and 150 mEq/liter for multivalent ions. In this regard, in certainparticularly preferred embodiments of the invention, the total saltconcentration is from about 75 mEq/L to about 140 mEq/L.

Free amino acids can be used in self-buffering IL-17RA antigen bindingprotein formulations in accordance with various embodiments of theinvention as bulking agents, stabilizers, and antioxidants, as well asother standard uses. However, amino acids included in self-bufferingIL-17RA antigen binding protein formulations do not provide bufferingaction. For this reason, those with significant buffer capacity eitherare not employed, are not employed at any pH around which they havesignificant buffering activity, or are used at low concentration sothat, as a result, their buffer capacity in the formulation is notsignificant. This is particularly the case for histidine and other aminoacids that commonly are used as buffers in pharmaceutical formulations.

Subject to the foregoing consideration, lysine, proline, serine, andalanine can be used for stabilizing proteins in a formulation. Glycineis useful in lyophilization to ensure correct cake structure andproperties. Arginine may be useful to inhibit protein aggregation, inboth liquid and lyophilized formulations. Methionine is useful as anantioxidant.

Polyols include sugars, e.g., mannitol, sucrose, and sorbitol andpolyhydric alcohols such as, for instance, glycerol and propyleneglycol, and, for purposes of discussion herein, polyethylene glycol(PEG) and related substances. Polyols are kosmotropic. They are usefulstabilizing agents in both liquid and lyophilized formulations toprotect proteins from physical and chemical degradation processes.Polyols also are useful for adjusting the tonicity of formulations.

Among polyols useful in select embodiments of the invention is mannitol,commonly used to ensure structural stability of the cake in lyophilizedformulations. It ensures structural stability to the cake. It isgenerally used with a lyoprotectant, e.g., sucrose. Sorbitol and sucroseare among preferred agents for adjusting tonicity and as stabilizers toprotect against freeze-thaw stresses during transport or the preparationof bulks during the manufacturing process. Reducing sugars (whichcontain free aldehyde or ketone groups), such as glucose and lactose,can glycate surface lysine and arginine residues. Therefore, theygenerally are not among preferred polyols for use in accordance with theinvention. In addition, sugars that form such reactive species, such assucrose, which is hydrolyzed to fructose and glucose under acidicconditions, and consequently engenders glycation, also is not amongpreferred amino acids of the invention in this regard. PEG is useful tostabilize proteins and as a cryoprotectant and can be used in theinvention in this regard, such as it is in Recombinate®.

Embodiments of the self-buffering IL-17RA antigen binding proteinformulations further comprise surfactants. Protein molecules may besusceptible to adsorption on surfaces and to denaturation and consequentaggregation at air-liquid, solid-liquid, and liquid-liquid interfaces.These effects generally scale inversely with protein concentration.These deleterious interactions generally scale inversely with proteinconcentration and typically are exacerbated by physical agitation, suchas that generated during the shipping and handling of a product.

Surfactants routinely are used to prevent, minimize, or reduce surfaceadsorption. Useful surfactants in the invention in this regard includepolysorbate 20, polysorbate 80, other fatty acid esters of sorbitanpolyethoxylates, and poloxamer 188.

Surfactants also are commonly used to control protein conformationalstability. The use of surfactants in this regard is protein-specificsince, any given surfactant typically will stabilize some proteins anddestabilize others.

Polysorbates are susceptible to oxidative degradation and often, assupplied, contain sufficient quantities of peroxides to cause oxidationof protein residue side-chains, especially methionine. Consequently,polysorbates should be used carefully, and when used, should be employedat their lowest effective concentration. In this regard, polysorbatesexemplify the general rule that excipients should be used in theirlowest effective concentrations.

Embodiments of the self-buffering IL-17RA antigen binding proteinformulations further comprise one or more antioxidants. To some extentdeleterious oxidation of proteins can be prevented in pharmaceuticalformulations by maintaining proper levels of ambient oxygen andtemperature and by avoiding exposure to light. Antioxidant excipientscan be used as well to prevent oxidative degradation of proteins. Amonguseful antioxidants in this regard are reducing agents,oxygen/free-radical scavengers, and chelating agents. Antioxidants foruse in therapeutic protein formulations in accordance with the inventionpreferably are water-soluble and maintain their activity throughout theshelf life of a product. EDTA is a preferred antioxidant in accordancewith the invention in this regard and can be used in the invention inmuch the same way it has been used in formulations of acidic fibroblastgrowth factor and in products such as Kineret® and Ontak®.

Antioxidants can damage proteins. For instance, reducing agents, such asglutathione in particular, can disrupt intramolecular disulfidelinkages. Thus, antioxidants for use in the invention are selected to,among other things, eliminate or sufficiently reduce the possibility ofthemselves damaging proteins in the formulation.

Formulations in accordance with the invention may include metal ionsthat are protein co-factors and that are necessary to form proteincoordination complexes, such as zinc necessary to form certain insulinsuspensions. Metal ions also can inhibit some processes that degradeproteins. However, metal ions also catalyze physical and chemicalprocesses that degrade proteins.

Magnesium ions (10-120 mM) can be used to inhibit isomerization ofaspartic acid to isoaspartic acid. Ca⁺² ions (up to 100 mM) can increasethe stability of human deoxyribonuclease (rhDNase, Pulmozyme®). Mg⁺²,Mn⁺², and Zn⁺², however, can destabilize rhDNase. Similarly, Ca⁺² andSr⁺² can stabilize Factor VIII, it can be destabilized by Mg⁺², Mn⁺² andZn⁺², Cu⁺² and Fe⁺², and its aggregation can be increased by Al⁺³ ions.

Embodiments of the self-buffering IL-17RA antigen binding proteinformulations further comprise one or more preservatives. Preservativesare necessary when developing multi-dose parenteral formulations thatinvolve more than one extraction from the same container. Their primaryfunction is to inhibit microbial growth and ensure product sterilitythroughout the shelf-life or term of use of the drug product. Commonlyused preservatives include benzyl alcohol, phenol and m-cresol. Althoughpreservatives have a long history of use with small-moleculeparenterals, the development of protein formulations that includespreservatives can be challenging. Preservatives almost always have adestabilizing effect (aggregation) on proteins, and this has become amajor factor in limiting their use in multi-dose protein formulations.To date, most protein drugs have been formulated for single-use only.However, when multi-dose formulations are possible, they have the addedadvantage of enabling patient convenience, and increased marketability.A good example is that of human growth hormone (hGH) where thedevelopment of preserved formulations has led to commercialization ofmore convenient, multi-use injection pen presentations. At least foursuch pen devices containing preserved formulations of hGH are currentlyavailable on the market. NORDITROPIN® brand Somatropin (liquid, NovoNordisk), NUTROPIN AQ® brand Somatropin (liquid, Genentech) &GENOTROPIN® brand Somatropin (lyophilized—dual chamber cartridge,Pharmacia & Upjohn) contain phenol while SOMATROPE® brand Somatropin(Eli Lilly) is formulated with m-cresol.

Several aspects need to be considered during the formulation anddevelopment of preserved dosage forms. The effective preservativeconcentration in the drug product must be optimized. This requirestesting a given preservative in the dosage form with concentrationranges that confer anti-microbial effectiveness without compromisingprotein stability. For example, three preservatives were successfullyscreened in the development of a liquid formulation for interleukin-1receptor (Type I) using differential scanning calorimetry (DSC). Thepreservatives were rank ordered based on their impact on stability atconcentrations commonly used in marketed products.

As might be expected, development of liquid formulations containingpreservatives are more challenging than lyophilized formulations.Freeze-dried products can be lyophilized without the preservative andreconstituted with a preservative containing diluent at the time of use.This shortens the time for which a preservative is in contact with theprotein, significantly minimizing the associated stability risks. Withliquid formulations, preservative effectiveness and stability have to bemaintained over the entire product shelf-life (˜18 to 24 months). Animportant point to note is that preservative effectiveness has to bedemonstrated in the final formulation containing the active drug and allexcipient components.

Self-buffering IL-17RA antigen binding protein formulations generallywill be designed for specific routes and methods of administration, forspecific administration dosages and frequencies of administration, forspecific treatments of specific diseases, with ranges ofbio-availability and persistence, among other things. Formulations thusmay be designed in accordance with the invention for delivery by anysuitable route, including but not limited to orally, aurally,opthalmically, rectally, and vaginally, and by parenteral routes,including intravenous and intraarterial injection, intramuscularinjection, and subcutaneous injection.

Compositions in accordance with the invention may be produced usingwell-known, routine methods for making, formulating, and using proteins,particularly pharmaceutical proteins. In certain of the preferredembodiments of a number of aspects of the invention in this regard,methods for preparing the compositions comprise the use of counter ionsto remove residual buffering agents. In this regard the term counter ionis any polar or charged constituent that acts to displace buffer fromthe composition during its preparation. Counter ions useful in thisregard include, for instance, glycine, chloride, sulfate, and phosphate.The term counter ion in this regard is used to mean much the same thingas displacement ion.

Residual buffering agents can be removed using the counter ions in thisregard, using a variety of well-known methods, including but not limitedto, standard methods of dialysis and high performance membranediffusion-based methods such as tangential flow diafiltration. Methodsfor residual buffer removal employing a counter ion in this regard canalso, in some cases, be carried out using size exclusion chromatography.

In certain related preferred embodiments in this regard, compositions inaccordance with the invention are prepared by a process that involvesdialysis against a bufferless solution at a pH below that of thepreparation containing the self-buffering protein. In particularlypreferred embodiments of the invention in this regard, the bufferlesssolution comprises counter ions, particularly those that facilitateremoval of residual buffer and do not adversely affect theself-buffering protein or the formulation thereof. In furtherparticularly preferred embodiments of the invention in this regard,following dialysis the pH of the preparation is adjusted to the desiredpH using dilute acid or dilute base.

In certain related particularly preferred embodiments in this regard,compositions in accordance with the invention are prepared by a processthat involves tangential flow diafiltration against a bufferlesssolution at a pH below that of the preparation containing theself-buffering protein. In particularly preferred embodiments of theinvention in this regard, the bufferless solution comprises counterions, particularly those that facilitate removal of residual buffer anddo not adversely affect the self-buffering protein or the formulationthereof. In further particularly preferred embodiments of the inventionin this regard, following diafiltration the pH of the preparation isadjusted to the desired pH using dilute acid or dilute base.

Once the pharmaceutical composition has been formulated, it may bestored in sterile vials as a solution, suspension, gel, emulsion, solid,crystal, or as a dehydrated or lyophilized powder. Such formulations maybe stored either in a ready-to-use form or in a form (e.g., lyophilized)that is reconstituted prior to administration. The invention alsoprovides kits for producing a single-dose administration unit. The kitsof the invention may each contain both a first container having a driedprotein and a second container having an aqueous formulation. In certainembodiments of this invention, kits containing single andmulti-chambered pre-filled syringes (e.g., liquid syringes andlyosyringes) are provided.

The therapeutically effective amount of an IL-17RA antigen bindingprotein-containing pharmaceutical composition to be employed willdepend, for example, upon the therapeutic context and objectives. Oneskilled in the art will appreciate that the appropriate dosage levelsfor treatment will vary depending, in part, upon the molecule delivered,the indication for which the IL-17RA antigen binding protein is beingused, the route of administration, and the size (body weight, bodysurface or organ size) and/or condition (the age and general health) ofthe patient. In certain embodiments, the clinician may titer the dosageand modify the route of administration to obtain the optimal therapeuticeffect. A typical dosage may range from about 0.1 μg/kg to up to about30 mg/kg or more, depending on the factors mentioned above. In specificembodiments, the dosage may range from 0.1 μg/kg up to about 30 mg/kg,optionally from 1 μg/kg up to about 30 mg/kg or from 10 μg/kg up toabout 5 mg/kg.

Dosing frequency will depend upon the pharmacokinetic parameters of theparticular IL-17RA antigen binding protein in the formulation used.Typically, a clinician administers the composition until a dosage isreached that achieves the desired effect. The composition may thereforebe administered as a single dose, or as two or more doses (which may ormay not contain the same amount of the desired molecule) over time, oras a continuous infusion via an implantation device or catheter. Furtherrefinement of the appropriate dosage is routinely made by those ofordinary skill in the art and is within the ambit of tasks routinelyperformed by them. Appropriate dosages may be ascertained through use ofappropriate dose-response data. In certain embodiments, the antigenbinding proteins of the invention can be administered to patientsthroughout an extended time period. Chronic administration of an antigenbinding protein of the invention minimizes the adverse immune orallergic response commonly associated with antigen binding proteins thatare not fully human, for example an antibody raised against a humanantigen in a non-human animal, for example, a non-fully human antibodyor non-human antibody produced in a non-human species.

The route of administration of the pharmaceutical composition is inaccord with known methods, e.g., orally, through injection byintravenous, intraperitoneal, intracerebral (intra-parenchymal),intracerebroventricular, intramuscular, intra-ocular, intraarterial,intraportal, or intralesional routes; by sustained release systems or byimplantation devices. In certain embodiments, the compositions may beadministered by bolus injection or continuously by infusion, or byimplantation device.

The composition also may be administered locally via implantation of amembrane, sponge or another appropriate material onto which the desiredmolecule has been absorbed or encapsulated. In certain embodiments,where an implantation device is used, the device may be implanted intoany suitable tissue or organ, and delivery of the desired molecule maybe via diffusion, timed-release bolus, or continuous administration.

It also may be desirable to use IL-17RA antigen binding proteinpharmaceutical compositions according to the invention ex vivo. In suchinstances, cells, tissues or organs that have been removed from thepatient are exposed to IL-17RA antigen binding protein pharmaceuticalcompositions after which the cells, tissues and/or organs aresubsequently implanted back into the patient.

In particular, IL-17RA antigen binding proteins can be delivered byimplanting certain cells that have been genetically engineered, usingmethods such as those described herein, to express and secrete thepolypeptide. In certain embodiments, such cells may be animal or humancells, and may be autologous, heterologous, or xenogeneic. In certainembodiments, the cells may be immortalized. In other embodiments, inorder to decrease the chance of an immunological response, the cells maybe encapsulated to avoid infiltration of surrounding tissues. In furtherembodiments, the encapsulation materials are typically biocompatible,semi-permeable polymeric enclosures or membranes that allow the releaseof the protein product(s) but prevent the destruction of the cells bythe patient's immune system or by other detrimental factors from thesurrounding tissues.

All references cited within the body of the instant specification arehereby expressly incorporated by reference in their entirety.

EXAMPLES

The following examples, including the experiments conducted and theresults achieved, are provided for illustrative purposes only and arenot to be construed as limiting the invention.

Example 1

IL-17RA knockout mice were generated as described in Ye et al., 2001, J.Exp. Med. 194:519-527 and tested in a standard collagen inducedarthritis (CIA) model. Briefly, Genomic clones encoding murine IL-17Rwere isolated from a 129 derived lambda library using a murine IL-17RcDNA probe and mapped by a combination of PCR, restriction digest, andsequence analyses using deposited genomic sequences corresponding toIL-17R locus on mouse chromosome 6 (GenBank/EMBL/DDBJ accession no.AC018559). A gene targeting vector was constructed by replacing 5.7 kbof genomic sequence containing exons 4-11 (corresponding to nucleotides445-1,172 of the murine IL-17R cDNA) with a PGKneo cassette. A thymidinekinase cassette (MC-TK) was inserted into the 5′ end of the vector. 129derived embryonic stem (ES) cells were electroporated with the targetingvector and selected in the presence of G418 and ganciclovir asdescribed. ES clones carrying a targeted mutation in IL-17R wereidentified by a combination of PCR and genomic Southern blot analysesand were injected into C57BL/6 blastocysts. The resulting male chimeraswere crossed to C57BL/6 females to generate mice heterozygous for theIL-17R mutation (IL-17R^(+/−)), which were subsequently intercrossed togenerate IL-17R-deficient mice (IL-17RKO). These mice were moved to aC57BL/6 background by five successive backcrosses to C57BL/6 mice.

IL-17RA knockout mice showed reduced mean clinical score in the CIAmodel, as shown in FIG. 4 (see also Kolls et al., 2001, J. Ex. Med.194:519-527; Lubberts at al., 2005, supra). In addition, the IL-17RAknockout mice showed only a 5% incidence of disease, whereas thewild-type mice showed a 71% incidence of disease.

Example 2

The histopathology of CIA-induced IL-17RA−/− mice and IL-17RA expressingmice was compared to determine the correlation between induced arthritisand the absence of IL-17RA signaling.

Mice were prepared as described in Example 1. The animals weresacrificed at fifteen to twenty weeks of age, and the histopathology ofjoints from the sacrificed animals were then examined. Histopathology ofbone and cartilage in IL-17RA−/− knock-out mice and IL-17A/IL-17Rexpression mice (WT C57/BL6 (No. 2-18)) showed subchondral bone erosionof the talus and marked joint architecture disruption oftarsal-metatarsal joints (subchondral bone and articular cartilageerosion), as well as reactive periosteal bone formation (osteophytosis).Histopathology of ankle joints from mice deficient in IL-17RA−/− in anexperimentally induced CIA model showed little joint inflammation andjoint cartilage and bone erosion. However, the histopathologic analysisof an ankle joint of the rear paw of IL-17RA expressing mice showedmarked chronic active inflammation. The significantly reduced incidenceof joint inflammation and joint and bone erosion as compared to WT micefurther implicates IL-17RA and IL-17RA signaling in inflammation anderosion.

Example 3

A model of MOG (Myelin Oligodendrocyte Glycoprotein)-peptide-induced EAEmodel mice deficient in IL-17RA showed a delay in the onset of arthritisas well as an overall reduction in clinical scores as compared to WTmice.

IL-17RA knockout mice were prepared as described in Example 1. FIG. 5shows the incidence and median onset of arthritis as a function of timefor both IL-17RA−/− and IL-17RA wild-type mice. 15 out of 15 of theIL-17RA expressing wild-type mice exhibited arthritic symptoms, with amean onset of 13 days. By contrast, 14 of 15 IL-17RA−/− mice exhibitedarthritic symptoms, with a mean onset of 22 days (p<0.0001 versuswild-type).

Clinical scores of IL-17RA−/− knockout mice show a lower mean clinicalscore, with a later onset, than wild-type mice. FIG. 6 shows reducedclinical scores in IL-17RA−/− knockout mice as compared to wild-typemice in a MOG-induced model. The IL-17RA−/− knockout population showed asignificantly later onset of arthritis than the IL-17RA expressingwild-type population. Further, the IL-17RA−/− knockout population had alower mean clinical score at all time points for onset of arthritis. Thelonger mean onset of arthritis and lower mean clinical score forarthritis observed in IL-17RA−/− mutants as compared toIL-17RA-expressing wild-type animals further implicates IL-17RAsignaling in inflammation and erosion.

Example 4

Ovalbumin sensitized and challenged IL-17RA KO mice show a significantreduction of inflammatory cells in BAL (bronchioalveolar lavage) fluidcompared to wild-type mice. IL-17RA KO mice were prepared as describedin Example 1, and then challenged intra-nasally with ovalbumin. Thenumber of inflammatory cells in the IL-17RA KO population were comparedto the IL-17RA expressing wild-type population. FIG. 7 shows IL-17RA KOmice have reduced total numbers of inflammatory cells in BAL fluid thanIL-17RA expressing wild-type mice in an ovalbumin-induced of asthmapost-third challenge.

The IL-17RA KO mouse population was compared to IL-17RA expressingwild-type mice for the incidence of eosinophils (A), neutrophils (B),lymphocytes (C) and macrophages (D) in BAL fluid in an ovalbumin-inducedmodel of asthma. FIGS. 8A-8D show that IL-17RA KO mice have reducednumbers of eosinophils (8A), neutrophils (8B) and lymphocytes (8C) inBAL fluid in the IL-17RA KO population as compared to the IL-17RAexpressing wild-type population. No changes in BAL fluid macrophage (8D)were noted in either wile-type or IL-17RA KO mice (naïve andOVA-challenged). These data suggest that IL-17RA signaling is importantin regulating immune-mediated inflammatory responses.

Example 5

IL-17RA antibodies were shown to reduce incidence of arthritis in a CIA(Collagen-Induced Arthritis) mouse model when administeredprophylactically and therapeutically. The IL-17RA inhibition reducedclinical arthritis in both a prophylactic and therapeutic manner forseveral models if CIA.

The surrogate neutralizing mouse IL-17RA mAb administeredprophylactically reduced mean clinical scores in wild-type CIA model ina dose-dependent manner. FIG. 9 shows the dose-dependent inhibition byIL-17RA mAb in wild-type CIA model. Mice were treated with eitherIL-17RA mAb or control Ig on a Monday, Wednesday and Friday schedule for2.5 weeks post boost. Administration of 100 μg and 300 μg of IL-17RAantibodies resulted in a lower clinical score for 18 days post-boostthan compared to isotype control Ig.

A reduction in bone loss and cartilage erosion in the joint wasassociated with the reduction of mean clinical scores at the 300 μg doseof the IL-17RA mAb. Histopathologic analysis and radiographic imagesanalysis were compared to the IgG control. By both means of analysis,the ankle joint of the near paw of CBA/1 male mouse treated with anIL-18R mAb (isotype control) showed marked inflammation: subchondrialbone erosion of the talus, marked joint architecture disruption oftarsal-metatarsal joints (subchondrial bone and articular cartilageerosion), and reactive periosteal bone formation (osteophytosis). Instark contrast, the ankle joint of the rear paw of a DBA/1 mouse treatedwith 300 μg anti-IL-17RA mAb showed well-defined joint spaces, lack ofedema and lack of periosteal reactive bone or lytic lesions indicatedreduced bone loss and cartilage erosion.

Example 6

IL-17RA inhibition was also shown to be effective in a CIA model whendosing was initiated after the onset of clinical signs (i.e, therapeuticdosing protocol) in a wild-type and TNFR p55/p75 KO model. Treatment wasinitiated approximately 6-7 days post collagen introduction in bothmodels. FIG. 10 shows that therapeutic treatment with anti-IL-17RA mAbstabilized mean clinical scores in both wild-type mice. FIG. 11 showsthat therapeutic treatment with anti-IL-17RA mAb stabilized meanclinical scores in TNFR p55/p75 KO models. Mice were treated with eitheran anti-IL-17RA mAb, anti-IL-1R mAb, or control Ig on a Monday,Wednesday and Friday schedule for 2 weeks post randomization intotherapeutic treatment groups. These data are representative of 2independent experiments performed in both WT and TNFR p55/p75 KO CIAmodels. Administering anti-IL-17RA mAbs showed a reduced clinical scoreas compared to control IgG in CIA induced wild-type mice. Surprisingly,the similar efficacy of anti-IL-17RA mAbs in the TNF p55/p75 KO modelstabilized CIA independently of TNF signaling. This data suggestsanti-IL-17RA antigen binding protein therapy may pick up non-respondersto anti-TNF therapies. Combination therapy of an anti-IL-17RA antigenbinding protein with anti-TNF therapies may be more beneficial thaneither alone.

Example 7

The development of fully human monoclonal antibodies directed againsthuman IL-17RA was carried out using Abgenix (now Amgen Fremont Inc.)XenoMouse® technology (U.S. Pat. Nos. 6,114,598; 6,162,963; 6,833,268;7,049,426; 7,064,244, which are incorporated herein by reference intheir entirety; Green et al, 1994, Nature Genetics 7:13-21; Mendez etal., 1997, Nature Genetics 15:146-156; Green and Jakobovitis, 1998, J.Ex. Med. 188:483-495)). TABLE 4 shows the portions of the IL-17RAprotein used as an immunogen and cell lines used to generate and screenanti-IL-17RA antibodies.

TABLE 4 Reagent Description IL-17RA.Fc Human IL-17RA extracellulardomain with a C-terminal human Fc domain. Expressed in a stable CHO cellline. IL-17RA-FLAG-polyHis Human IL-17RA extracellular domain (SEQ IDNO: 431) with a C-terminal FLAG-polyHis tag. Expressed by transienttransfection in COS PKB cells. IL-17RA CHO cells Human IL-17RAfull-length expressed on the surface of CHO cells.

IgG2 XenoMouse® mice were immunized/boosted with IL-17RA-Fc (group 1)and IL-17RA-FLAG-polyHis (group 2). Serum titers were monitored by ELISAand mice with the best titers were fused to generate hybridomas. Theresulting polyclonal supernatants were screened for binding to IL-17RAby ELISA, and the positive supernatants were screened for binding toIL-17RA CHO cells by FMAT. Positive supernatants were subjected toadditional screening. IgG2 XenoMouse® mice were immunized with thefollowing immunogens: IL-17RA-Fc (group 3) and IL-17RA-FLAG-pHis (group4) and were tested following additional immunizations.

Example 8

The anti-IL-17RA antibodies were characterized. Non-clonal hybridomasupernatants were prepared in volumes of 1-2 mls (the Ig concentrationswere not determined for these supernatants). The anti-IL-17RA non-clonalhybridoma supernatants were initially screened by FACS for their abilityto inhibit biotinylated human IL-17A binding to CHO cellsover-expressing human IL-17RA and another CHO cell line over-expressingcynomolgus IL-17RA. Nonclonal supernatants that were able to completelyor nearly completely inhibit binding of human IL-17A to CHO-huIL-17RAand CHO-cynoIL-17RA were subsequently screened at several dilutions inan IL-17A-induced cytokine/chemokine secretion assay using a humanforeskin fibroblast (HFF) cell line. Anti-IL-17RA non-clonalsupernatants were incubated with HFF cells (5000 cells/well in 96 wellplate) for 30 minutes at 36° C. and then stimulated overnight witheither IL-17A (5 ng/ml) alone or IL-17F (20 ng/ml) and TNF-alpha (5ng/ml). Fibroblast culture supernatants were then analyzed by ELISA forthe presence of either IL-6 or GRO-alpha. Anti-IL-17RA non-clonalhybridomas were selected for sub-cloning based on their performance inthe CHO-IL-17RA FACS assay and HFF bioassay. An example of the selectionis shown in TABLES 5, 6, and 7.

TABLE 5 HFF % positive % positive MFI Bioassay Neg. Cntl. 1.09 1.57 10Repeat assays IL-17 biot. (500 ng/ml) 8.85 10.22 77 1:4 dil. 1:32 1:41:32 1:128 % inhibition of IL-6 production Supernatant I.D.  1 1.34 1.789 56 14  2 (incl. AM_(H)15/AM_(L)15) 0.60 3.77 6 80 72 98 91 81  3 1.041.60 8 46 −5  4 (incl. AM_(H)14/AM_(L)14) 1.72 0.79 10 90 82 99 92 84  51.59 1.43 11 76 52  6 1.45 1.93 14 82 79  7 1.00 1.28 8 71 58  8 1.431.60 14 69 31  9 1.34 2.28 18 59 20 10 0.79 1.96 11 58 −2 11 1.93 1.6911 72 21 12 2.23 1.69 8 69 7 13 (incl. 1.49 0.49 6 82 53AM_(H)21/AM_(L)21) 14 1.01 1.25 8 63 23 15 1.31 1.45 9 74 45 16 1.390.72 8 58 4 17 0.91 0.94 7 73 38 18 1.37 2.85 13 49 6 19 1.47 1.15 8 7461 20 1.60 1.20 7 72 46 21 1.30 1.65 8 47 4 22 0.93 1.02 8 54 16 23 1.081.12 7 72 59

In TABLE 5, anti-IL-17RA non-clonal hybridoma supernatants were screenedfor binding to IL-17RA. The first half of TABLE 5 shows the % positiveand mean fluorescent intensity (MFI) in results from flow cytometry(i.e, FACS). The % positive shows inhibition of biotin-huIL-17A bindingto huIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. TheMFI column shows inhibition of biotinylated huIL-17A binding to cynoIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. The secondhalf of TABLE 5 shows the HFF binding intensity for the non-clonal andmAbs as measured by the % intensity of IL-6 production. The first 2columns show an IL-17A/HFF bioassay with non-clonal hybridomasupernatants and the last 4 columns are repeat IL-17A/HFF bioassayresults with non-clonal hybridoma supernatants.

TABLE 6 FACS results on 293-Cyno IL-17RA-expressing Cells % % positivepositive MFI HFF bioassay repeat 1:4 dilution 1:32 1:4 1:32 1:128 1:512% inhibition of IL-6 production Neg. Cntl 1.09 1.57 1.0 IL-17biot. (500ng/ml) 8.85 10.22 77 Supernatant I.D.  1 (incl. 1.32 1.4 9AM_(H)11/AM_(L)11)  2 0.87 2.92 9  3 1.0 4.47 16  4 1.03 5.01 17  5 0.66.53 18  6 (incl. 0.73 4.55 9 AM_(H)5/AM_(L)5)  7 0.59 5.18 8  8 0.457.25 7  9 2.34 2.36 6 61 36 10 6.76 8.35 64 37 12 11 0.78 1.16 6 61 2412 0.61 1.64 6 74 56 71 67 45 35 13 2.98 5.48 22 −2 −13 14 5.34 10.64 4922 2 3 39 31 34 15 0.5 3.24 11 51 −7 16 (incl. 0.54 2.93 18 92 72 91 7373 29 AM_(H)22/AM_(L)22) 17 1.25 2.2 17 −8 −76 18 0.61 0.99 7 73 28 19(incl. AM_(H)23) 0.69 1.72 10 79 72 86 76 67 50 20 1.53 1.94 31 5 −31 216.66 9.63 66 −15 4 22 6.33 10.32 71 1 14 23 0.3 2.55 7 50 35 24 0.244.11 6 34 15 25 0.81 0.99 8 −49 11 26 0.43 1.31 7 67 48 27 0.7 1.23 1150 26 28 0.58 1.32 9 56 47 29 (incl. 0.8 1.85 11 77 76 90 87 79 66AM_(H)1/AM_(L)1) 30 0.69 1.55 11 40 16 31 0.56 1.96 12 12 −11 32 0.211.11 8 46 7 33 1.24 1.15 13 68 43 34 0.74 0.81 11 36 8 35 0.71 1.37 9 6521 36 0.57 1.21 7 78 32 37 0.59 1.0 8 71 3 38 0.65 1.43 8 63 −38 39 0.281.23 7 43 −21 40 0.35 2.48 9 50 −39 41 0.64 1.61 8 49 −19 42 0.12 1.04 887 68 96 92 80 66 43 0.21 1.12 11 79 34 44 0.32 1.33 8 68 −3 45 0.741.68 10 40 −16 46 0.58 1.74 10 64 7

TABLE 6 shows IL-17RA non-clonal hybridoma supernatant screening data.The % positive and MFI columns show results from flow cytometry (FACS).The % positive columns show inhibition of biotin-huIL-17A binding tohuIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. The MFIcolumn shows inhibition of biotinylated huIL-17A binding to cynoIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. The first 2HFF bioassay columns are IL-17A/HFF bioassay with non-clonal hybridomasupernatants and the last 4 bioassay columns are repeat IL-17A/HFFbioassay results with selected non-clonal hybridoma supernatants. Anumber of supernatants were selected for sub-cloning.

TABLE 7 % positive MFI HFF bioassay Neg. Cntl 1.09 1.57 10 IL-17biot.(500 ng/ml) 8.85 10.22 77 1:4 1:32 1:128 % inhibition of IL-6 ProductionSupernatant I.D.  1 1.85 1.33 10 29 9 21  2 1.08 1.46 16 90 61 50  31.29 1.39 22 33 10 4  4 1.55 1.33 18 53 66 58  5 1.69 0.7 8 76 46 30  6(incl. AM_(H)13/AM_(L)13) 1.52 0.89 6 73 78 75  7 1.54 0.98 7 79 71 45 8 1.78 3.44 34 73 63 30  9 6.34 8.45 53 57 48 34 10 1.23 1.58 10 82 7131 11 1.62 2.1 28 −10 −6 −10 12 1.15 1.04 16 71 63 37 13 2.43 1.67 12 5823 −4 14 1.43 1.03 13 42 17 18 15 1.62 1.59 18 67 59 31 16 1.79 2.2 2561 57 45 17 0.91 1.85 10 49 54 23 18 (incl. AM_(H)12/AM_(L)12) 1 1.36 675 82 61 19 (incl. AM_(H)17/AM_(L)17) 1.75 1.23 8 90 81 73 20 2.31 0.499 35 20 38 21 (incl. AM_(H)16/AM_(L)16) 1.84 0.76 6 86 90 71

TABLE 7 shows anti-IL-17RA non-clonal hybridoma supernatant screeningdata. The first two columns are flow cytometry data (FACS). The %positive columns show inhibition of biotin-huIL-17A binding tohuIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. The MFIcolumn shows inhibition of biotinylated huIL-17A binding to cynomolgusIL-17RA⁺ CHO cells by the non-clonal hybridoma supernatants. The finalthree columns show IL-17A/HFF bioassay results with non-clonal hybridomasupernatants. Supernatants 6, 18, 19 and 21 were selected forsubcloning.

TABLE 8 IL-17A/HFF Low resolution bioassay BIAcore Sub-clone ID IC₅₀(nM) K_(D) (nM)  1. Subclone of (AM_(H)14/AM_(L)14) 0.12 0.69  2.Subclone of (AM_(H)14/AM_(L)14)2 0.20 ND  3. Subclone of(AM_(H)14/AM_(L)14)3 0.075 ND  4. Subclone of (AM_(H)21/AM_(L)21) 2.3 ND 5. Subclone of (AM_(H)21/AM_(L)21) 3.1 ND  6. Subclone of(AM_(H)21/AM_(L)21) 3.3 16.7  7. Subclone of (AM_(H)20/AM_(L)20) 8.1 ND 8. Subclone of (AM_(H)20/AM_(L)20) 6.6 ND  9. Subclone of(AM_(H)20/AM_(L)20) 6.7 11.6 10. Subclone of (AM_(H)19/AM_(L)19) 0.223.1 11. Subclone of (AM_(H)19/AM_(L)19) 1.1 ND 12. Subclone of(AM_(H)19/AM_(L)19) 0.50 ND 13. Subclone of (AM_(H)13/AM_(L)13) >10 7.614. Subclone of (AM_(H)18/AM_(L)18) 0.44 ND 15. Subclone of(AM_(H)18/AM_(L)18) 0.40 ND 16. Subclone of (AM_(H)18/AM_(L)18) 0.1714.9 17. Subclone of (AM_(H)12/AM_(L)12) 3.5 ND 18. Subclone of(AM_(H)12/AM_(L)12) 3.7 8.2 20. Subclone of (AM_(H)12/AM_(L)12) 5.5 ND21. Subclone of (AM_(H)17/AM_(L)17) 2.5 8.2 22. Subclone of(AM_(H)17/AM_(L)17) 5.3 ND 23. Subclone of (AM_(H)17/AM_(L)17) 0.57 ND24. Subclone of (AM_(H)16/AM_(L)16) 1.6 ND 25. Subclone of(AM_(H)16/AM_(L)16) 2.3 6.2 26. Subclone of (AM_(H)16/AM_(L)16) 1.4 ND27. Subclone of (AM_(H)22/AM_(L)22) 0.046 1.5 28. Subclone of(AM_(H)22/AM_(L)22) 0.09 ND 29. Subclone of (AM_(H)22/AM_(L)22) 0.07 NDND = not determined

TABLE 8 shows IL-17A/HFF bioassay IC50 values and low resolutionBIAcore® K_(D) values for subcloned hybridomas. Lower IC50 and K_(D)values in the IL-17A/HFF IL-17RA binding assays showed that the IL-17RAmAbs inhibited binding of IL-17A to IL-17 receptor A. Antibodies wereselected for further characterization based on low K_(D) values forinhibiting IL-17A binding to human IL-17RA.

Example 9

IL-17RA human mAb clones having the heavy and light chain sequences(AM_(H)22/AM_(L)22), (AM_(H)19/AM_(L)19), (AM_(H)18/AM_(L)18) and(AM_(H)14/AM_(L)14) were selected for further bioassay characterization.TABLE 9 below shows IC50 values for the selected Abs in the HFF bioassayand a primary lung fibroblast bioassay against both IL-17A and IL-17F.

TABLE 9 IL-17A/HFF IL-17F/HFF IL-17A/lung IL-17RA mAb IC50 (nM) IC50(nM) fibroblast IC50 (nM) (AM_(H)14/AM_(L)14) 0.13 0.067 0.04(AM_(H)22/AM_(L)22) 0.10 0.033 0.14 (AM_(H)19/AM_(L)19) 0.20 0.087 0.22(AM_(H)18/AM_(L)18) 0.33 0.073 0.081

The selected human mAbs inhibited IL-17A binding to IL-17RA. In additionto the lower IC50 values observed for IL-17A binding to IL-17RA, theselected human mAbs exhibited reduced IC50 values inhibiting the bindingof IL-17F to IL-17RA (second column). Therefore, the selected human mAbsinhibit both IL-17A-IL-17RA binding and IL-17F-IL-17RA binding.

Example 10

Exemplary IL-17RA human mAbs were tested in a cynomolgus bioassayutilizing the cynomolgus-derived kidney epithelial cell line JTC-12stimulated with cynomolgus IL-17A. FIG. 12 shows IL-17RA mAbs having theheavy and light chain sequences (AM_(H)22/AM_(L)22),(AM_(H)19/AM_(L)19), (AM_(H)18/AM_(L)18) and (AM_(H)14/AM_(L)14) in theinhibition of cynomolgus IL-17A-induced IL-6 production from JTC-12cells. The (----) line depicts the positive control value ofcynomologous IL-17 in combination with TNF-alpha. The (-.-.-) linedepicts the positive control value of cynomologous TNF-alpha. The ( . .. ) line depicts the media control value. JTC-12 cells were preincubatedfor 30 mins with anti-IL-17RA mAbs and then stimulated overnight withcynomolgus IL-17A (5 ng/ml) and human TNF-alpha (5 ng/ml). FIG. 12 showsthat each antibody was able to inhibit cynomolgous IL-17A from bindingIL-17RA and inhibit IL-17RA activation, as determined by IL-6 productionfrom JTC-12 cells. The IL-17RA antibody (AM_(H)14/AM_(L)14) was able toantagonize cynomolgous IL-17A-induced IL-6 production from JTC-12 cellswith an IC50 of approximately 1.2 nM.

Example 11

In vitro binding of IL-17RA mAbs was assayed. The binding affinities ofIL-17RA antibodies were measured by surface plasmon resonance using aBiacore 3000® instrument by standard methods known in the art. Antibodycandidates were captured on CM4 chips derivatized with goat anti-humanIgG (H+L) antibody (Jackson Immuno Research, Bar Harbor, Me.). A CM4chip coated with goat anti-human IgG (H+L) antibody but without capturedantibody was used as a reference. Soluble huIL-17RA-FLAG-polyHis (SEQ IDNO:431) at a concentration range of 0.46-1000 nM was flowed over thechips for 2 minutes (association phase) followed by a 15-30 minutedisassociation phase. FLAG peptide, Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys(DYKDDDDK) (SEQ ID NO:447) as described in Hopp et al., Bio/Technology6:1204, 1988, and U.S. Pat. No. 5,011,912 enables rapid assay and facilepurification of expressed recombinant protein. Reagents useful forpreparing fusion proteins in which the FLAG peptide is fused to a givenpolypeptide are commercially available (Sigma, St. Louis, Mo.).

Experiments were conducted at 25° C. using a 50 uL/min flow rate. Datawas fit to a 1:1 Model+Local Rmax using BIAeval Software® (v4.1).

TABLE 10 Human Antibody k_(a) (1/Ms) K_(D) (1/s) K_(A) (1/M) K_(D) (M)(AM_(H)14/AM_(L)14) 2.60 × 10⁵ 6.22 × 10⁻⁵ 4.18 × 10⁹ 2.39 × 10⁻¹⁰(AM_(H)22/AM_(L)22) 2.35 × 10⁵ 1.17 × 10⁻⁴ 2.01 × 10⁹ 4.98 × 10⁻¹⁰(AM_(H)19/AM_(L)19) 1.42 × 10⁵ 1.14 × 10⁻⁴ 1.25 × 10⁹ 8.02 × 10⁻¹⁰(AM_(H)18/AM_(L)18) 1.02 × 10⁵ 1.01 × 10⁻³ 1.01 × 10⁸ 9.88 × 10⁻⁹

TABLE 10 shows the K_(D) of the human mAb clones was on the order of10⁻¹⁰ to 10⁻⁹, with the clone having the heavy and light chain sequences(AM_(H)14/AM_(L)14) having the highest affinity. Each of the humanmonoclonal antibodies' kinetic data was consistent with the equilibriumdata. The antibody with the heavy and light chain variable sequences(AM_(H)14/AM_(L)14; SEQ ID NO:14 and SEQ ID NO:40, respectively) had thehighest affinity for IL-17RA, as well as the slowest off-rate.

Example 12

The agonistic potential of IL-17RA human mAb having the heavy and lightchain variable sequences (AM_(H)14/AM_(L)14) was assessed in vitro. TheIL-17RA mAb (AM_(H)14/AM_(L)14) was tested for its agonist effects onHFF cells. IL-17RA mAb having the heavy and light chain sequences(AM_(H)14/AM_(L)14) was also tested under conditions of cross-linkingwith goat anti-human F(ab′)², goat anti-human IgG and mouse anti-humanIgG prior to incubation on HFF cells. Recombinant L-17RA mAbAM_(H)14/AM_(L)14 at 0, 0.1, 0.5, 1, 1.5 and 10 μg/ml, alone andpre-cross linked with murine anti-human IgG (Zymed/invitrogen, SanDiego, Calif.), goat anti-human F(ab′)² (Goat a-h-Fab) and goatanti-human IgG (Goat a-h IgG) were incubated overnight with HFF cells.GRO-alpha was assessed by ELISA. IL-17A alone served as a positivecontrol for GRO-alpha production in this experiment. These data arerepresentative of 2 independent experiments. IL-17RA mAb(AM_(H)14/AM_(L)114) alone had no effect on HFF cells. Pre-crosslinkinganti-IL-17RA mAb (AM_(H)14/AM_(L)14) had no effect on GRO-alphaproduction from HFF cells. These data demonstrate that anti-IL-17RA mAb(AM_(H)14/AM_(L)14) either alone or pre-cross-linked and incubated withHFF cells was unable to induce a GRO-alpha response and therefore is notan agonistic mAb to IL-17RA.

Example 13

The effects of the germline (GL) changes to IL-17RA mAbAM_(H)14/AM_(L)14 were tested in the HFF bioassay. FIG. 13 showssequence variation in the framework regions of SEQ ID NO:40 (AM_(L)14)in relation to germline residues and the effect on IC50 values. SEQ IDNO:40 (AM_(L)14) contains four non-germline residues in the framework,two in FR2 and two in FR3. Standard site-directed mutagenesis methodswere used to generate germline versions A and B of AM_(H)14/AM_(L)14.These variants were tested in the IL-17A and IL-17F HFF bioassay: HFFcells were preincubated for 30 mins with various anti-IL-17RA mAbs andthen stimulated overnight with IL-17 (5 ng/ml).

FIG. 14 shows that the two variants that had the residues returned togermline (see FIG. 13) had reduced IL-17A inhibitory activity inrelation to AM_(H)14/AM_(L)14, indicating that some variation in theframework regions was tolerated but that some residues may influenceactivity. The (----) line indicates the positive control value of IL-17stimulation in the absence of antibody (approximately 4062 pg/ml). Themedia-only control gave a value of approximately 71 pg/ml.

FIG. 15 shows that the two variants that had the residues returned togermline (see FIG. 13) had reduced IL-17F inhibitory activity inrelation to AM_(H)14/AM_(L)14, indicating that some variation in theframework regions was tolerated but that some residues may influenceactivity. The positive control value of IL-17F in combination withTNF-alpha stimulation in the absence of antibody was approximately 10994pg/ml, the value for TNF-alpha only was approximately 1534 pg/ml, andthe media-only control gave a value of approximately 55 pg/ml.

Example 14

Studies were conducted to determine where the various IL-17RA antigenbinding proteins (in the form of human antibodies) bound to humanIL-17RA. The ForteBio™ Octet System is one of several systems andtechniques available for measuring antibody binding. The methods usedfor screening antibody binding essentially followed the manufacturer'srecommendations. For more information see www.fortebio.com. In brief,streptavidin sensors (ForteBio™) were presoaked for 10 minutes in PBSAT(1% BSA/PBS+0.05% Tween20® (polyoxyethylene sorbitan monolaurate).Biotinylated AM_(H)14/AM_(L)14 at 10 ug/mL in PBSAT was loaded onto thesensors for 900 seconds. A new baseline was run for 600 seconds inPBSAT. Wild-type IL-17RA-FLAG-polyHis (SEC ID NO:431) at 10 ug/mL inPBSAT was then bound to the sensors for 900 seconds. A new baseline wasestablished for 600 seconds in PBSAT. 200 nM of the following mAbsAM_(H)22/AM_(L)22, AM_(H)19/AM_(L)19, and AM_(H)18/AM_(L)18 wereassociated for 900 seconds, followed by dissociation for 900 seconds inPBSAT. The data showed that AM_(H)18/AM_(L)18 did not compete withAM_(H)14/AM_(L)14 for binding, showing that AM_(H)14/AM_(L)14 andAM_(H)18/AM_(L)18 bind to different neutralizing determinants.AM_(H)22/AM_(L)22 and AM_(H)19/AM_(L)19 did not bind in the presence ofAM_(H)14/AM_(L)14, suggesting that all three of these antibodies bind tothe same or to a similar neutralizing determinant and therefore areconsidered to bin together.

Example 15

Cross-competition studies were performed to determine IL-7RA bindingcharacteristics of exemplary IL-17RA antibodies. A modification of themultiplexed binding method described by Jia, et al. was used (see Jia,et al., J. Immun. Meth., 2004, 288:91-98). The method employed theBio-Plex Workstation and software (BioRad, Hercules, Calif.), as well asreagents from Luminex® Corp. (Austin, Tex.). The manufacturers' basicprotocols were followed except where noted below (see www.bio-rad.comand www.luminexcorp.com for details). Each bead code ofstreptavidin-coated Luminex® beads (Luminex®, #L100-L1XX-01, where “XX”specifies the bead code) were incubated in 150 ul of 50 ug/mlbiotinylated monovalent mouse-anti-human IgG capture antibody (BDPharmingen, Becton Dickinson, Franklin Lakes, N.J., product #555785) for1 hour at room temperature in the dark and then washed 3 times withPBSAT. The mouse-anti-human IgG coating was evaluated and the beadsquantified by FACS. Each bead code was separately incubated with 10 ulof anti-IL-17RA antibody for 1 hour at room temperature and then washed.The beads were pooled and then dispensed to a 96-well filter plate(Millipore, Billerica, Mass., product #MSBVN1250). 80 ul of 2 ug/mlIL-17RA (SEQ ID NO:431) was added to half the wells and buffer to theother half and incubated at room temperature for 1 hour then washed withPBSAT. 10 ul of an anti-IL-17RA antibody was added to one well withIL-17RA (SEQ ID NO:431) and one well without IL-17RA and incubated atroom temperature for 1 hour then washed with PBSAT. An irrelevanthuman-IgG (Jackson Labs., Bar Harbor, Me., product #009-000-003) wasincluded as a negative control. 50 ul PE-conjugated monovalentmouse-anti-human IgG (BD Pharmingen, Becton Dickinson, Franklin Lakes,N.J., #555787) was added to each well and incubated at room temperaturefor 1 hour and then washed with PBSAT. The PE-tagged monovalent antibodywill detect the presence of the second mAb added to the well, but notthe first mAb captured by the monovalent mouse-anti-human IgG antibody.Beads were resuspended in 120 ul PBSAT and at least 100 events/bead codewere collected on the Bio-Plex workstation as per the manufacturer'srecommended protocol.

Median Fluorescent Intensity (MFI) of the antibody pair without IL-17RAwas subtracted from the MFI signal of the corresponding reactioncontaining IL-17RA to normalize for background noise. The criteria fordetermining if two antibodies cross-competed with each other andtherefore “binned” together was a matter of determining the degree towhich the second antibody was detectable. If the normalized MFI washigher than the highest of any of the following three values, then theanti-IL-17RA antibodies were considered to be simultaneously bound toIL-17RA and were considered to be in different bins (i.e., theantibodies did not cross-compete): the normalized MFI is greater than 3times the MFI value of the antibody paired with itself, or 3 times theMFI value of the antibody paired with a huIgG control, or a MFI of 300.Generally speaking, antibodies assigned to different bins bind differentparts of IL-17RA and antibodies assigned to the same bin(s) bind similarparts of IL-17RA.

FIGS. 16A and 16B show the results of multiplexed binding ofanti-IL-17RA antibodies. Shaded values indicate antibody pairs that bindto IL-17RA simultaneously, suggesting that these antibodies bind todifferent neutralizing determinants. Boxed values indicate antibodiespaired against themselves and cross-compete. The following monoclonalhuman antibodies containing the ascribed heavy and light variabledomains were tested: A: AM_(H)11/AM_(L)11, B: AM_(H)4/AM_(L)4, C:AM_(H)8/AM_(L)8, D: AM_(H)7/AM_(L)7, E: AM_(H)6/AM_(L)6, F:AM_(H)10/AM_(L)10, G: AM_(H)18/AM_(L)18, H: AM_(H)1/AM_(L)1, I:AM_(H)22/AM_(L)22, J: AM_(H)23/AM_(L)23, K: AM_(H)14/AM_(L)14, L:AM_(H)19/AM_(L)19, M: AM_(H)12/AM_(L)12, N: AM_(H)17/AM_(L)17, O:AM_(H)16/AM_(L)16, P: AM_(H)26/AM_(L)26, Q: AM_(H)21/AM_(L)21, and R:AM_(H)20/AM_(L)20.

FIGS. 16A and 16B also show that antibodies A: AM_(H)11/AM_(L)11, B:AM_(H)4/AM_(L)4, C: AM_(H)8/AM_(L)8, D: AM_(H)7/AM_(L)7, E:AM_(H)6/AM_(L)6, F: AM_(H)10/AM_(L)10, and G: AM_(H)18/AM_(L)18 competedwith one another for binding to human IL-17RA and as a consequence fellinto a defined group (Bin 1). In general, antibodies I:AM_(H)22/AM_(L)22, J: AM_(H)23/AM_(L)23, K: AM_(H)14/AM_(L)14, L:AM_(H)19/AM_(L)19, M: AM_(H)12/AM_(L)12, N: AM_(H)17/AM_(L)17, O:AM_(H)16/AM_(L)16 competed with one another for binding to human IL-17RAand as a consequence fell into a defined group (Bin 3). Generallyspeaking, the antibodies of Bin 1 did not compete with the antibodies ofBin 3.

Antibody H: AM_(H)1/AM_(L)1 was unique in its competition pattern andformed Bin 2, but is most similar to Bin 3. Antibody P:AM_(H)26/AM_(L)26 formed Bin 4 and showed little cross-competition withany of the other antibodies, suggesting a neutralizing determinantunique to this antibody. Antibodies Q: AM_(H)21/AM_(L)21 and R:AM_(H)20/AM_(L)20, showed individually unique competition patterns, butwith considerable similarities to Bin 3 antibodies, and formed Bins 5and 6, respectively. This data provides evidence of several specieswithin a subgenus of cross-competing antibodies.

Example 16

As described above, antibodies that bind human IL-17RA and inhibit, orneutralize, the binding of IL-17A and/or IL-17F were created andcharacterized. To determine the neutralizing determinants on humanIL-17RA that these various IL-17RA antibodies bound, a number ofchimeric human/mouse IL-17RA proteins were constructed. This methodtakes advantage of the non-cross reactivity of the various IL-17RAantibodies with mouse IL-17RA. For each chimera, one or two regions ofhuman IL-17RA extracellular domain (SEQ ID NO:431) was/were replacedwith the corresponding region(s) of mouse IL-17RA (SEQ ID NO:432). FIG.17 shows mouse IL-17RA (SEQ ID NO:432) and the 5 domains, A, B, C, D, E,and F that replaced the counterpart domains in the human IL-17RAsequence. Such techniques are known in the art, see for example Stemmer,W. P. C. et al., 1995 Gene 164:49-53.

Six single-region and 8 double-region chimeras were constructed in pTT5vectors. Chimeric constructs A through F (single region chimeras) weremade synthetically by PCR annealing of 65-mer sense and antisenseoligonucleotides which span the protein from a Sal1 site 5′ of theinitiation codon to a Not1 site 3′ of the termination codon. Thetemplate used in the first round of PCR was a mix of oligos (sense andantisense) spanning the region from the Sal1 site to the Not1 site. PCRwas done in 2 steps as follows:

Double chimeric constructs were made by digestion of single chimeras Athrough D with Sal1 and Sac1 restriction enzymes and a 3-way ligationwith Sac1 and Not1 digested chimeras E and F using pTT5 as theexpression vector. The chimeras, huIL-17RA-FLAG-polyHis (SEQ ID NO:431),and muIL-17RA-FLAG-polyHis (SEQ ID NO:432) were expressed transientlyusing 2936-E cells (available from the National Research Council ofCanada (NRCC); see NRCC document L-11565 for further information) ashost cells in roller bottles. Such transient expression techniques arewell known in the art, see for example Durocher, Y. et al., 2002 NucleicAcids Res. January 15; 30(2):E9. The supernatants were purified using aHisTrap™ HP column as per the manufacturer's general guidelines (GEHealthcare, Piscataway N.J.) and eluted using a standard imidazolegradient (see manufacturer's recommended protocols). Purified proteinwas desalted into PBS, pH 7.2.

The chimeras were aligned using standard analysis tools, such asClustalW (EMBL-EBI). The resulting chimeric proteins are shown in FIGS.18A-18D. With reference to FIGS. 17 and 18A-18D, Chimera A (SEQ IDNO:433) is human IL-17RA extracellular domain with mouse Domain A;Chimera B (SEQ ID NO:434) is human IL-17RA extracellular domain withmouse Domain B; Chimera C (SEQ ID NO:435) is human IL-17RA extracellulardomain with mouse Domain C; Chimera D (SEQ ID NO:436) is human IL-17RAextracellular domain with mouse Domain D; Chimera E (SEQ ID NO:437) ishuman IL-17RA extracellular domain with mouse Domain E; Chimera F (SEQID NO:438) is human IL-17RA extracellular domain with mouse Domain F;Chimera G (SEQ ID NO:439) is human IL-17RA extracellular domain withmouse Domains A and E; Chimera H (SEQ ID NO:440) is human IL-17RAextracellular domain with mouse Domains B and E; Chimera I (SEQ IDNO:441) is human IL-17RA extracellular domain with mouse Domains C andE; Chimera J (SEQ ID NO:442) is human IL-17RA extracellular domain withmouse Domains D and E; Chimera K (SEQ ID NO:443) is human IL-17RAextracellular domain with mouse Domains A and F; Chimera L (SEQ IDNO:444) is human IL-17RA extracellular domain with mouse Domains B andF; Chimera M (SEQ ID NO:445) is human IL-17RA extracellular domain withmouse Domains C and F; and Chimera N (SEQ ID NO:446) is human IL-17RAextracellular domain with mouse Domains D and F.

Using methods similar to those described in Example 15, multiplexanalysis using the Bio-Plex Workstation and software (BioRad, Hercules,Calif.) was performed to determine neutralizing determinants on humanIL-17RA by analyzing exemplary human IL-17RA mAbs differential bindingto chimeric versus wild-type IL-17RA proteins. Twelve bead codes ofpentaHis-coated beads (Qiagen, Valencia, Calif.; see www1.qiagen.com)were used to capture histidine-tagged protein. The 12 bead codes allowedthe multiplexing of II chimeric and the wild type human IL-17RA.

To prepare the beads, 100 ul of wild-type IL-17RA supernatant fromtransient expression culture and 100 ul of 2.5 ug/ml chimeric proteinwere bound to penta-His-coated beads overnight at 4° C. or 2 hours atroom temperature with vigorous shaking. The beads were washed as per themanufacturer's protocol and the 12 bead set was pooled and aliquotedinto 2 or 3 columns of a 96-well filter plate (Millipore, Billerica,Mass., product #MSBVN1250) for duplicate or triplicate assay points,respectively. 100 ul anti-IL-17RA antibodies in 4-fold dilutions wereadded to the wells, incubated for 1 hour at room temperature, andwashed. 100 ul of a 1:100 dilution of PE-conjugated anti-human IgG Fc(Jackson Labs., Bar Harbor, Me., product #109-116-170) was added to eachwell, incubated for 1 hour at room temperature and washed. Beads wereresuspended in 1% BSA, shaken for 3 minutes, and read on the Bio-Plexworkstation. Antibody binding to IL-17RA chimeric protein was comparedto antibody binding to the human IL-17RA wild-type from the same pool. Atitration of antibody over approximately a 5 log scale was performed.Median Fluorescence Intensity (MFI) of chimeric proteins was graphed asa percent of maximum wild-type human IL-17RA signal. Mutations (i.e.,mouse domains) that increase the EC50 (expressed in nM) for the IL-17RAmAb by 3-fold or greater (as calculated by GraphPad Prism®) wereconsidered to have negatively affected IL-17RA mAb binding. Throughthese methods, neutralizing determinants for various IL-17RA antibodieswere elucidated.

FIG. 19 is a table summarizing the IL-17RA mAbs capacity to bind thevarious chimeric proteins. Shaded values denote where the IL-17RA mAbdid not meet the criteria for binding to that particular chimericprotein (“n.d.,” i.e., “not determined” means that the chimera was notassayed). As described above, EC50 values are provided. A zero valueindicates that antibody binding was ablated. The underlined value wasassigned an EC50 value by the GraphPad Prism® even though the titrationcurve was essentially flat. TABLE 11 shows the control values in nM forthe assay.

TABLE 11 huWT 3× wt 2× wt mAb mu WT ctrl ctrl ctrl AM_(H)18/AM_(L)180.000 0.061 0.182 0.121 AM_(H)1/AM_(L)1 1.879 0.134 0.403 0.269AM_(H)22/AM_(L)22 0.000 0.043 0.128 0.085 AM_(H)14/AM_(L)14 3416.0000.027 0.082 0.055 AM_(H)19/AM_(L)19 770.100 0.062 0.187 0.125AM_(H)23/AM_(L)23 0.000 0.053 0.158 0.106 AM_(H)26/AM_(L)26 0.000 0.2810.843 0.562 AM_(H)21/AM_(L)21 0.196 0.018 0.055 0.037 AM_(H)20/AM_(L)201.333 0.022 0.066 0.044

As can be seen in FIG. 19, at least three neutralizing determinants wereidentified based on those regions affecting the binding of neutralizingIL-17RA antibodies, namely Domain B spanning amino acids 75-96 of humanIL-17RA (SEQ ID NO:431), Domain C spanning amino acids 128-154 of humanIL-17RA (SEQ ID NO:431), and Domain D spanning amino acids 176-197 ofhuman IL-17RA (SEQ ID NO:431). Domain B spanning amino acids 75-96 ofhuman IL-17RA (SEQ ID NO:431) negatively affected the binding ofneutralizing antibodies AM_(H)1/AM_(L)1 and AM_(H)23/AM_(L)23. Domain Cspanning amino acids 128-154 of human IL-17RA (SEQ ID NO:431) negativelyaffected the binding of neutralizing antibodies AM_(H)22/AM_(L)22 andAM_(H)23/AM_(L)23. Domain D spanning amino acids 176-197 of humanIL-17RA (SEQ ID NO:431) negatively affected the binding of neutralizingantibodies AM_(H)1/AM_(L)1, AM_(H)22/AM_(L)22, AM_(H)14/AM_(L)14,AM_(H)19/AM_(L)19, AM_(H)23/AM_(L)23, AM_(H)21/AM_(L)21, andAM_(H)20/AM_(L)20. The binding characteristics of the IL-17RA antibodiesin relation to where the antibodies bound on human IL-17RA was confirmedby the double chimeras. Thus, Domain B, C, and D are consideredneutralizing determinants.

Example 17

As described above, antibodies that bind human IL-17RA and inhibit, orneutralize, the binding of IL-17A and/or IL-17F were created andcharacterized. To determine the neutralizing determinants on humanIL-17RA that these various IL-17RA antibodies bound, a number of mutantIL-17RA proteins were constructed having arginine substitutions atselect amino acid residues of human IL-17RA. Arginine scanning is anart-recognized method of evaluating where antibodies, or other proteins,bind to another protein, see for example Nanevicz, T., et al., 1995, J.Biol. Chem., 270:37, 21619-21625 and Zupnick, A., et al., 2006, J. Biol.Chem., 281:29, 20464-20473. In general, the arginine sidechain ispositively charged and relatively bulky as compared to other aminoacids, which may disrupt antibody binding to a region of the antigenwhere the mutation is introduced. Arginine scanning is a method thatdetermines if a residue is part of a neutralizing determinant and/or anepitope.

95 amino acids distributed throughout the human IL-17RA extracellulardomain were selected for mutation to arginine. The selection was biasedtowards charged or polar amino acids to maximize the possibility of theresidue being on the surface and reduce the likelihood of the mutationresulting in misfolded protein. FIG. 20 depicts the amino acid residuesthat were replaced with an arginine residue in SEQ ID NO:431. Usingstandard techniques known in the art, sense and anti-senseoligonucleotides containing the mutated residues were designed based oncriteria provided by Stratagene Quickchange® II protocol kit(Stratagene/Agilent, Santa Clara, Calif.). Mutagenesis of the wild-type(WT) HuIL-17RA-Flag-pHis was performed using a Quickchange® II kit(Stratagene). All chimeric constructs were constructed to encode aFLAG-histidine tag (six histidines) on the carboxy terminus of theextracellular domain to facilitate purification via the poly-His tag.

Multiplex analysis using the Bio-Plex Workstation and software (BioRad,Hercules, Calif.) was performed to determine neutralizing determinantson human IL-17RA by analyzing exemplary human IL-17RA mAbs differentialbinding to arginine mutants versus wild-type IL-17RA proteins. Twelvebead codes of pentaHis-coated beads (Qiagen, Valencia, Calif.; seewww1.qiagen.com) were used to capture histidine-tagged protein. The 12bead codes allowed the multiplexing of II IL-17RA arginine mutants andwild-type human IL-17RA (SEQ ID NO:431).

To prepare the beads, 100 ul of wild-type IL-17RA and IL-17RA argininemutant supernatants from transient expression culture were bound topenta-His-coated beads overnight at 4° C. or 2 hours at room temperaturewith vigorous shaking. The beads were washed as per the manufacturer'sprotocol and the 12 bead set was pooled and aliquoted into 2 or 3columns of a 96-well filter plate (Millipore, Bellerica, Mass., product#MSBVN1250) for duplicate or triplicate assay points, respectively. 100ul anti-IL-17RA antibodies in 4-fold dilutions were added to the wells,incubated for 1 hour at room temperature, and washed. 100 ul of a 1:100dilution of PE-conjugated anti-human IgG Fc (Jackson Labs., Bar Harbor,Me., product #109-116-170) was added to each well, incubated for 1 hourat room temperature and washed. Beads were resuspended in 1% BSA, shakenfor 3 minutes, and read on the Bio-Plex workstation. Antibody binding toIL-17RA arginine mutant protein was compared to antibody binding to thehuman IL-17RA wild-type from the same pool. A titration of antibody overapproximately a 5 log scale was performed. Median Fluorescence Intensity(MFI) of IL-17RA arginine mutant proteins was graphed as a percent ofmaximum wild-type human IL-17RA signal. Those mutants for which signalfrom all the antibodies are below 30% of wild-type IL-17RA were deemedto be either of too low a protein concentration on the bead due to poorexpression in the transient culture or possibly misfolded and wereexcluded from analysis: these were T51R, K53R,55R, H64R, D75R, E110R,Q118R, T121, E123R, S147R, H148R, E158R, T160R, H163R, K191R, T193R,E213R, H251R, T269R, H279R, and D293R. Mutations (i.e., argininesubstitutions) that increase the EC50 for the IL-17RA mAb by 3-fold orgreater (as calculated by GraphPad Prism®) were considered to havenegatively affected IL-17RA mAb binding. Through these methods,neutralizing determinants and epitopes for various IL-17RA antibodieswere elucidated.

FIG. 21 illustrates titration curves of various IL-17RA mAbs binding tothe D152R IL-17RA mutant (i.e., the aspartic acid at position 152 of SEQID NO:431 was mutagenized to be an arginine). AntibodiesAM_(H)1/AM_(L)1, AM_(H)22/AM_(L)22, AM_(H)14/AM_(L)14,AM_(H)19/AM_(L)19, AM_(H)23/AM_(L)23, AM_(H)21/AM_(L)21, andAM_(H)20/AM_(L)20 lost the capacity to bind the D152R IL-17RA mutant.Antibodies AM_(H)18/AM_(L)18 and AM_(H)26/AM_(L)26 were only marginallyaffected but did not meet the cutoff criteria.

A summary of the arginine scan, binding, and chimera data is presentedin FIG. 22. The arginine scan methodology identified severalneutralizing determinants: AM_(H)18/AM_(L)18 bound a domain spanningamino acids 220-284 of human IL-17RA (SEQ ID NO:431); AM_(H)1/AM_(L)1bound a domain focused on amino acid residue 152 of human IL-17RA (SEQID NO:431); AM_(H)22/AM_(L)22 bound a domain spanning amino acids152-198 of human IL-17RA (SEQ ID NO:431); AM_(H)14/AM_(L)14 bound adomain spanning amino acids 152-297 of human IL-17RA (SEQ ID NO:431);AM_(H)19/AM_(L)19 bound a domain spanning amino acids 152-186 of humanIL-17RA (SEQ ID NO:431); AM_(H)23/AM_(L)23 bound a domain spanning aminoacids 97-297 of human IL-17RA (SEQ ID NO:431); AM_(H)26/AM_(L)26 bound adomain spanning amino acids 138-270 of human IL-17RA (SEQ ID NO:431);AM_(H)21/AM_(L)21 bound a domain spanning amino acids 113-198 of humanIL-17RA (SEQ ID NO:431); and AM_(H)20/AM_(L)20 bound a domain spanningamino acids 152-270 of human IL-17RA (SEQ ID NO:431).

All of the residues shown in FIG. 22 have been shown to ablate bindingof a neutralizing human monoclonal antibody that specifically binds tohuman IL-17RA.

What is claimed is:
 1. A method of treating COPD, comprisingadministering to a patient having COPD a pharmaceutical compositioncomprising an human monoclonal antibody selected from the group: a. anisolated antibody, comprising a light chain variable domain sequencecomprising SEQ ID NO:40 and a heavy chain variable domain sequencecomprising SEQ ID NO:14; and b. an isolated antibody, comprising a lightchain CDR1 comprising SEQ ID NO:224, a light chain CDR2 comprising SEQID NO:225, a light chain CDR3 comprising SEQ ID NO:226, a heavy chainCDR1 comprising SEQ ID NO:146, a heavy chain CDR2 comprising SEQ IDNO:147 and a heavy chain CDR3 comprising SEQ ID NO:148, wherein saidantibody specifically binds to human IL-17 receptor A and inhibits thebinding of IL-17A to said IL-17 receptor A.
 2. The method of claim 1,further comprising administering to said patient a second treatmentcomprising a pharmaceutical composition, wherein said second treatmentis administered prior to, concurrent with, or subsequent toadministration of said pharmaceutical composition comprising saidantibody and wherein said antibody is: a. an IgG1 antibody; b. an IgG2antibody; c. an IgG3 antibody; or d. an IgG4 antibody.
 3. The method ofclaim 1, wherein said antibody is: a. an antigen-binding antibodyfragment; b. a single chain antibody; c. a diabody; d. a triabody; e. atetrabody; f. a Fab fragment; g. a F(ab′)2 fragment; h. an IgD antibody;i. an IgE antibody; j. an IgM antibody; k. an IgG1 antibody; l. an IgG2antibody; m. an IgG3 antibody; or n. an IgG4 antibody.
 4. The method ofclaim 1, wherein said antibody is: a. an IgG1 antibody; or b. an IgG2antibody.
 5. The method of claim 1, wherein said pharmaceuticalcomposition further comprises a pharmaceutically acceptable diluent. 6.The method of claim 1, wherein said antibody is a human IgG2 monoclonalantibody.
 7. The method of claim 1, wherein the antibody comprises alight chain sequence encoded by a polynucleotide comprising nucleotides84-741 of SEQ ID NO:428 and a heavy chain sequence encoded by apolynucleotide comprising SEQ ID NO:426, wherein said antibody isproduced from a Chinese Hamster Ovary Cell (CHO cell), and wherein saidantibody specifically binds to human IL-17 receptor A and inhibits thebinding of IL-17A to said IL-17 receptor A.
 8. The method of claim 7,further comprising administering to said patient a second treatmentcomprising a pharmaceutical composition, wherein said second treatmentis administered prior to, concurrent with, or subsequent toadministration of said composition comprising said antibody.
 9. Themethod of claim 7, wherein said composition pharmaceutical compositionfurther comprises a pharmaceutically acceptable diluent.
 10. The methodof claim 7, wherein said antibody is a human IgG2 monoclonal antibody.11. The method of claim 7, wherein said antibody is glycosylated. 12.The method of claim 7, wherein said composition pharmaceuticalcomposition further comprises a pharmaceutically acceptable diluent. 13.A method of treating COPD, comprising administering to a patient havingCOPD a pharmaceutical composition comprising an isolated humanmonoclonal antibody comprising a light chain CDR1 comprising SEQ IDNO:224, a light chain CDR2 comprising SEQ ID NO:225, a light chain CDR3comprising SEQ ID NO:226, a heavy chain CDR1 comprising SEQ ID NO:146, aheavy chain CDR2 comprising SEQ ID NO:147 and a heavy chain CDR3comprising SEQ ID NO:148, wherein said antibody specifically binds tohuman IL-17 receptor A and inhibits the binding of IL-17A to said IL-17receptor A.
 14. The method of claim 13, further comprising administeringto previously presented aid patient a second treatment comprising apharmaceutical composition, wherein said second treatment isadministered prior to, concurrent with, or subsequent to administrationof said composition comprising said antibody.
 15. The method of claim13, wherein said pharmaceutical composition further comprises apharmaceutically acceptable diluent.
 16. The method of claim 13, whereinsaid antibody is: a. an IgG1 antibody; b. an IgG2 antibody; c. an IgG3antibody; or d. an IgG4 antibody.
 17. The method of claim 13, whereinsaid antibody is a human IgG2 monoclonal antibody.
 18. A method oftreating COPD comprising administering to a patient having COPD acomposition comprising an isolated antibody comprising a light chainvariable domain sequence comprising SEQ ID NO:40 and a heavy chainvariable domain sequence comprising SEQ ID NO:14, wherein said antibodyspecifically binds to human IL-17 receptor A and inhibits the binding ofIL-17A to said IL-17 receptor A.
 19. The method of claim 18, furthercomprising administering to said patient a second treatment comprising apharmaceutical composition wherein said second treatment is administeredprior to, concurrent with, or subsequent to administration of saidcomposition comprising said antibody.
 20. The method of claim 18,wherein said composition comprises a pharmaceutically acceptablediluent.
 21. The method of claim 18 wherein said antibody is: a. a humanantibody; b. a humanized antibody; c. a chimeric antibody; d. amonoclonal antibody; e. an antigen-binding antibody fragment; f. asingle chain antibody; g. a Fab fragment; h. a F(ab′)2 fragment; i. anIgG1 antibody; or j. an IgG2 antibody.
 22. The method of claim 18,wherein said antibody is a human antibody.
 23. The method of claim 18,wherein said antibody is a monoclonal antibody.
 24. The method of claim18, wherein said antibody is a human monoclonal antibody.
 25. The methodof claim 18, wherein said antibody is a human IgG2 monoclonal antibody.26. The method of claim 18, wherein said composition is a pharmaceuticalcomposition.
 27. The method of claim 26, wherein said pharmaceuticalcomposition further comprises a pharmaceutically acceptable diluent. 28.The method of claim 18, wherein the antibody comprises an isolatedantibody comprising a light chain sequence comprising amino acids 21-234of SEQ ID NO: 429 and a heavy chain sequence comprising SEQ ID NO: 427,wherein said antibody specifically binds to human IL-17 receptor A andinhibits the binding of IL-17A to said IL-17 receptor A.
 29. The methodof claim 28, further comprising administering to said patient a secondtreatment comprising a pharmaceutical composition wherein said secondtreatment is administered prior to, concurrent with, or subsequent toadministration of said composition comprising said antibody.
 30. Themethod of claim 28, wherein said antibody is: a. an IgG1 antibody b. anIgG2 antibody; or g. an IgG2 antibody.
 31. The method of claim 30,wherein said antibody is a human IgG2 monoclonal antibody.
 32. Themethod of claim 28, wherein said pharmaceutical composition furthercomprises a pharmaceutically acceptable diluent.